Novel tricyclic diazepines tocolytic oxytocin receptor antagonists

ABSTRACT

This invention provides novel tricyclic diazepine compounds as well as methods and pharmaceutical compositions utilizing these compounds for the treatment and/or prevention and/or suppression of disorders which may be remedied or alleviated by oxytocin antagonist activity, including treatment of preterm labor, dysmenorrhea, endometritis, and for suppressing labor prior to caesarean delivery. These compounds are also useful in enhancing fertility rates, enhancing survival rates and synchronizing estrus in farm animals; and may be useful in the prevention and treatment of disfunctions of the oxytocin system in the central nervous system including obsessive compulsive disorder (OCD) and neuropsychiatric disorders.

[0001] This application claims priority from copending provisionalapplication Serial No. 60/283,264, filed Apr. 12, 2001, the entiredisclosure of which is hereby incorporated by reference

[0002] This invention concerns novel tricyclic diazepines which act ascompetitive oxytocin receptor antagonists, as well as methods of theirmanufacture, methods of treatment and pharmaceutical compositionsutilizing these compounds. The compounds of the present invention areuseful therapeutic agents in mammals, particularly in humans. Morespecifically, they can be used in the prevention and/or suppression ofpreterm labor, for the suppression of labor at term prior to caesareandelivery, to facilitate antinatal transport to a medical facility, andfor the treatment of dysmenorrhea. These compounds also useful inenhancing fertility rates, enhancing survival rates and synchronizingestrus in farm animals; and may be useful in the prevention andtreatment of disfunctions of the oxytocin system in the central nervoussystem including obsessive compulsive disorder (OCD) andneuropsychiatric disorders.

BACKGROUND OF THE INVENTION

[0003] Premature labor remains the leading cause of perinatal mortalityand morbidity. Infant mortality dramatically decreases with increasedgestational age. The survival rate of prematurely born infants increasesfrom 20% at 24 weeks to 94% at 30 weeks. Moreover the cost associatedwith the care of an infant born prematurely is extremely high. Whilemany agents have been developed for the treatment of premature labor inthe last 40 years, the incidence of pre-term births and low birth weightinfants has remained relatively unchanged. Therefore there remains anunmet need for the development of a safe and effective treatment ofpreterm labor.

[0004] Tocolytic (uterine relaxing) agents currently in use include β₂adrenergic receptor agonists such as Ritodrine which is moderatelyeffective in suppressing preterm labor, but it is associated withmaternal hypotension, tachycardia, and metabolic side effects. Severalother agents have been used to suppress premature labor, including otherβ₂ adrenergic agonists (terbutaline, albuterol), magnesium sulfate,NSAIDs (indomethacin), and calcium channel blockers. The consensus isthat none of these agents are very effective; there is no clinicalevidence showing that these compounds can prolong gestation for morethan 7 days (Johnson, Drugs, 45, 684-692 (1993)). Furthermore, theirsafety profile is not ideal. Adverse effects include respiratorydepression and cardiac arrest (magnesium sulfate), hemodynamic effects(calcium channel blockers), premature closure of the ductus arteriosusand oligohydramnios (NSAIDs; prostaglandin synthase inhibitors).Therefore, there is an unmet need for safer and more efficacious agentsfor the treatment of preterm labor with better patient tolerability.Specific requirements with regard to safety include a product with no orlow rates of tachycardia, limited anxiety, improved fetal safety, andfew, if any, adverse cardiovascular effects.

[0005] One target of interest is the oxytocin receptor in the uterus,and a selective oxytocin receptor antagonist has been proposed as anideal tocolytic agent. While the exact role of oxytocin (OT) inparturition has not been clearly defined, there is evidence stronglysuggesting that it may play a critical role in the initiation andprogression of labor in humans (Fuchs et al. Science 215,1396-1398(1982); Maggi et al. J. Clin. Endocrinol. Metab. 70, 1142-1154 (1990);Åkerlund, Reg. Pept. 45, 187-191 (1993); Åkerlund, Int. Congr. Symp.Semin. Ser., Progress in Endocrinology 3, 657-660 (1993); Åkerlund etal., in Oxytocin, Ed. R. Ivell and J. Russel, Plenum Press, New York, pp595-600 (1995)). Preliminary clinical trials with oxytocin receptorantagonists support the concept that a blockade of OT receptors reducesuterine myometrial activity and delays the onset of labor (Åkerlund etal., Br. J. Obst. Gynaecol. 94, 1040-1044, (1987); Andersen et al., Am.J. Perinatol. 6, 196-199 (1989); Melin, Reg. Pept. 45, 285-288 (1993)).Thus, a selective oxytocin antagonist is expected to block the majoreffects of oxytocin exerted mainly on the uterus at term, and to be moreefficacious than current therapies for the treatment of preterm labor.By virtue of its direct action on the receptors in the uterus anoxytocin antagonist is also expected to have fewer side effects and animproved safety profile.

[0006] The following prior art references describe peptidic oxytocinantagonists: Hruby et al., Structure-Activity Relationships ofNeurohypophyseal Peptides, in The Peptides: Analysis, Synthesis andBiology; Udenfriend and Meienhofer Eds., Academic Press, New York, Vol.8, 77-207 (1987); Pettibone et al., Endocrinology, 125, 217 (1989);Manning et al., Synthesis and Some Uses of Receptor-Specific Agonistsand Antagonists of Vasopressin and Oxytocin, J. Recept. Res., 13,195-214 (1993); Goodwin et al., Dose Ranging Study of the OxytocinAntagonist Atosiban in the Treatment of Preterm Labor, Obstet Gynecol.,88, 331-336 (1996). Peptidic oxytocin antagonists suffer from a lack oforal activity and many of these peptides are non-selective antagonistssince they also exhibit vasopressin antagonist activity. Bock et al. [J.Med. Chem. 33, 2321 (1990)], Pettibone et al. [J. Pharm. Exp. Ther. 256,304 (1991)], and Williams et al. [J. Med. Chem., 35, 3905 (1992)] havereported on potent hexapeptide oxytocin antagonists which also exhibitweak vasopressin antagonistic activity in binding to V₁ and V₂receptors.

[0007] Various non-peptidic oxytocin antagonists and/oroxytocin/vasopressin (AVP) antagonists have recently been reported byPettibone et al., Endocrinology, 125, 217 (1989); Yamamura et al.,Science, 252, 572-574 (1991); Evans et al., J. Med. Chem., 35, 3919-3927(1992); Pettibone et al., J. Phannacol. Exp. Ther, 264, 308-314 (1992);Ohnishi et al., J. Clin. Pharmacol. 33, 230-238, (1993); Evans et al.,J. Med. Chem. 36, 3993-4006 (1993); Pettibone et al., Drug Dev. Res. 30,129-142 (1993); Freidinger et al., General Strategies in PeptidomimeticDesign: Applications to Oxytocin Antagonists, in Perspect. Med. Chem.179-193 (1993), Ed. B. Testa, Verlag, Basel, Switzerland;Serradeil-Legal, J. Clin. Invest, 92, 224-231 (1993); Williams et al.,J. Med. Chem. 37, 565-571 (1994); Williams et al., Bioorg. Med. Chem. 2,971-985 (1994); Yamamura et al., Br. J. Pharmacol., 105, 546-551 (1995);Pettibone et al., Advances in Experimental Medicine and Biology 395,601-612 (1995); Williams et al., J. Med. Chem. 38, 4634-4636 (1995);Hobbs et al., Biorg. Med. Chem. Lett. 5, 119 (1995); Williams et al.,Curr. Pharm. Des. 2, 41-58 (1996); Freidinger et al., Medicinal ResearchReviews, 17, 1-16 (1997); Pettibone et al., Biochem. Soc. Trans. 25 (3),1051-1057 (1997); Bell et al., J. Med. Chem. 41, 2146-2163 (1998); Kuoet al., Bioorg. Med. Chem. Lett. 8, 3081-3086 (1998); Williams et al.,Biorg. Med. Chem. Lett. 9, 1311-1316 (1999).

[0008] Certain carbostyril derivatives and bicyclic azepines aredisclosed as oxytocin and vasopressin antagonists by Ogawa et al. in WO94/01113 (1994); benzoxazinones are disclosed as oxytocin andvasopressin receptor antagonists by Sparks et al. in WO 97/25992 (1997);Williams et al. disclose piperidine oxytocin and vasopressin receptorantagonists in WO 96/22775 (1996); Bock et al. disclose benzoxazinoneand benzopyrimidinone piperidines useful as oxytocin and vasopressinreceptor antagonists in U.S. Pat. No. 5,665,719 (1997); piperazines andspiropiperidines useful as oxytocin and vasopressin receptor antagonistsare disclosed by Evans et al. in U.S. Pat. No. 5, 670,509 (1997) and byBock et al. in U.S. Pat. No. 5,756,504 (1998); Bell et al. disclosepiperazine oxytocin receptor antagonists in UK Patent Application, GB 2326 639 A (1998); Bell et al. disclose benzoxazinone and quinolinoneoxytocin and vasopressin receptor antagonists in UK Patent ApplicationGB 2 326 410 A (1998); Bell et al. disclose benzoxazinone oxytocin andvasopressin receptor antagonists in U.S. Pat. No. 5,756,497 (1998);Matsuhisa et al. disclose difluoro tetrahydrobenzazepine derivatives asoxytocin antagonists in WO 98/39325 (1998); Ogawa et al. discloseheterocyclic bisamides with vasopressin and oxytocin antagonist activityin U.S. Pat. No. 5,753,644 (1998)); and Ogawa et al. disclosebenzazepine derivatives with anti-vasopressin activity, oxytocinantagonistic activity and vasopressin agonist activity, useful asvasopressin antagonists, vasopressin agonists and oxytocin antagonistsin WO 97/22591 (1997) and U.S. Pat. No. 6,096,736 (2000).

[0009] Trybulski et al. disclose 3-carboxamide derivatives ofpyrrolobenzodiazepine bisamides with vasopressin antagonist activity inU.S. Pat. No. 5,880,122 (1999); bicyclic thienoazepines with vasopressinand oxytocin receptor antagonist activity are disclosed by Albright etal. in WO 96/22294 (1996) and U.S. Pat. No. 5,654,297 (1997); andtricyclic benzazepines with vasopressin and oxytocin receptor antagonistactivity are disclosed by Albright et al. in U.S. Pat. No. 5,849,735(1998).

[0010] Albright et al. broadly disclose tricyclic benzazepinevasopressin antagonists in WO 96/22282A1 (1996) which possessantagonistic activity at the V₁ and/or V₂ receptors and exhibit in vivovasopressin antagonistic activity, as well as antagonistic activity atthe oxytocin receptors.

[0011] Venkatesan et al. broadly disclose tricyclic benzazepines withvasopressin and oxytocin antagonist activity in U.S. Pat. No. 5,521,173(1996), WO 96/22292 (1996), and in U.S. Pat. No. 5,780,471 (1998) whichpossess antagonistic activity at the V₁ and/or V₂ receptors and exhibitin vivo vasopressin antagonistic activity, as well as antagonisticactivity at the oxytocin receptors.

[0012] Compounds which behave as potent oxytocin antagonists by bindingwith high affinity and selectivity to the oxytocin receptors, thuspreventing oxytocin from binding to its receptors and exerting itsbiological and pharmacologic effects in vivo, can be useful for thetreatment and/or prevention and/or suppression of preterm labor, for thesuppression of term labor prior to a caesarian delivery, and tofacilitate antinatal transport to a medical facility. They also canproduce contraception in mammals given that oxytocin antagonists havebeen shown to inhibit the release of oxytocin-stimulated luteneizinghormone (LH) from pituitary cells (Rettori et al., Proc. Nat Acad. Sci.U.S.A. 94, 2741-2744 (1997); Evans et al., J. Endocrinol., 122, 107-116(1989); Robinson et al., J. Endocrinol. 125, 425-432 (1990)).

[0013] Oxytocin antagonists have the ability to relax uterinecontractions induced by oxytocin in mammals and thus can be also usefulfor the treatment of dysmenorrhea, a condition characterized by painduring menstruation (Åkerlund, Int. Congr. Symp. Semin. Ser., Progressin Endocrinology 3, 657-660 (1993); Åkerlund, Reg. Pept. 45, 187-191(1993); Melin, Reg. Pept. 45, 285-288 (1993)). Primary dysmenorrhea isassociated with ovulatory cycles, and it is the most common complaint ofgynecologic patients. Myometrial hypercontractility and decreased bloodflow to the uterus are thought to be causative factors for for thesymptoms of primary dysmenorrhea (Åkerlund, Acta Obstet. Gynecol. Scand.66, 459-461 (1987). In particular, vasoconstriction of small uterinearteries by vasopressin and oxytocin is thought to produce tissueischemia and pain (Jovanovic et al., Br. J. Pharmacol. 12, 1468-1474(91997); Chen et al., Eur. J. Pharmacol. 376, 25-51 (1999)).

[0014] The administration of oxytocin receptor antagonists to farmanimals after fertilization has been found to enhance fertility rates byblocking oxytocin induced luteolysis leading to embryonic loss (Hickeyet al., WO 96/09824 Al (1996), Sparks et al., WO 97/25992 Al (1997);Sparks et al., U.S. Pat. No. 5,726,172 A (1998)). Thus, oxytocinreceptor antagonists can be useful in farm animal husbandry to controltiming of parturition and delivery of newborns resulting in enhancedsurvival rates. They can also be useful for the synchronization ofestrus by preventing oxytocin induced corpus luteum regression and bydelaying estrus (Okano, J. Reprod. Dev. 42 (Suppl.), 67-70 (1996)).Furthermore oxytocin receptor antagonists have been found to have apowerful effect in inhibiting oxytocin-induced milk ejection in dairycows (Wellnitz et al., Journal of Dairy Research 66, 1-8 (1999)).

[0015] Oxytocin is also synthesized in the brain and released in thecentral nervous system. Recent studies have established the importanceof central oxytocin in cognitive, affiliative, sexual and reproductivebehavior, and in regulating feeding, grooming and response to stress inanimals. Oxytocin may also influence normal behavior inhumans.Modulators of oxytocin binding to its receptors in the centralnervous system may be useful in the prevention and treatment ofdisfunctions of the oxytocin system, including obsessive compulsivedisorder (OCD) and other neuropsychiatric disorders (Kovacs et al.,Psychoneuroendocrinology23, 945-962 (1998); McCarthy et al., U.K. Mol.Med. Today 3, 269-275 (1997); Bohus, Peptidergic Neuron, [Int. Symp.Neurosecretion], 12^(th) (1996), 267-277, Publ. Birkhauser, Basel,Switz.; Leckman et al., Psychoneuroendocrinology 19, 723-749 (1994)).

[0016] Competitive inhibitors of vasopressin binding to its receptorsare useful in the treatment or prevention of state diseases involvingvasopressin disorders in mammals, which include vasodilation andaquaresis (free-water diuresis), treating hypertension and inhibitingplatelet aggregation. They are also useful in the treatment ofcongestive heart failure, cirrhosis with ascites, and in the syndrome ofinappropriate secretion of antiduretic hormone (SIADH). Furthermore,vasopressin receptor antagonists have been found to be useful intreating disturbances or illnesses of the inner ear, particularly thoserelated to Meniere's disease (Zenner et al., WO 99/24051-A2 (1999)); andfor the prevention and treatment of ocular circulatory disorders,particularly intraocular hypertension or glaucoma and vision disorderssuch as shortsightedness (Ogawa et al., WO 99/38533-A1 (1999)); Ohtakeet al., WO 99/65525 (1999)).

SUMMARY OF THE INVENTION

[0017] This invention comprises compounds of Formula (I):

[0018] R₁ and R₂ are, independently, selected from hydrogen,(C₁-C₆)lower alkyl, halogen, cyano, trifluoromethyl, hydroxy, amino,(C₁-C₆) lower alkylamino, (C₁-C₆) lower alkoxy, —OCF₃, (C₁-C₆) loweralkoxy carbonyl, —NHCO[(C₁-C₆)lower alkyl], carboxy, —CONH₂,—CONH[(C₁-C₆) lower alkyl], or -CON[(C₁-C₆) lower alkyl]₂;

[0019] R₃ is a substituent selected from hydrogen, (C₁-C₆) lower alkyl,(C₁-C₆) lower alkoxy, hydroxy, amino, (C₁-C₆) lower alkylamino, —COlower alkyl (C₁-C₆), or halogen;

[0020] R₄ consists of the moiety B-C; wherein:

[0021] B is selected from the group of:

[0022] wherein:

[0023] A is CH or N;

[0024] R₅, R_(6,) R₇, R₈, R₉, R₁₀ are, independently, selected fromhydrogen, (C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy, (C₁-C₆) lower alkylcarbonyl, (C₃-C₆) lower alkenyl, (C₃-C₆) lower alkynyl, hydroxy (C₁-C₆)lower alkyl, alkoxy (C₁-C₆) lower alkyl, acyloxy (C₁-C₆) lower alkyl,(C₃-C₈) cycloalkyl, formyl, cycloalkylcarbonyl, carboxy, lower alkoxycarbonyl, cycloalkyloxycarbonyl, aryl alkyloxycarbonyl, carbamoyl, —O—CH₂—CH═CH₂, halogen, halo lower alkyl, trifluoromethyl, —OCF₃,—S[(C₁-C₆) lower alkyl], —OC(O)N[(C₁-C₆) lower alkyl]₂, —CONH[(C₁-C₆)lower alkyl], —CON[(C₁-C₆) lower alkyl]₂, (C₁-C₆) lower alkylamino,di-[(C₁-C₈) lower alkyl]amino, (C₁-C₆) lower alkyl di-[(C₁-C₆) loweralkyl]amino, hydroxy, cyano, trifluoromethylthio, nitro, amino, (C₁-C₆)lower alkylsulfonyl, aminosulfonyl, (C₁-C₆) lower alkylaminosulfonyl,

[0025] phenyl or naphthyl;

[0026] and R is selected from —OH, NHOR₃₆, or any of the followinggroups:

[0027] wherein:

[0028] R₁, and R₁₂ are, independently, selected from hydrogen, (C₁-C₆)lower alkyl, (C₃-C₆) lower alkenyl, (C₃-C₈) cycloalkyl optionally mono-or di-[(C₁-C₆) loweralkyl] substituted, bicycloalkyl including but notlimited to adamantanyl, adamantane lower alkyl, bornyl, norbornyl, orquinuclidyl;

[0029] cycloalkyl lower alkyl, halo lower alkyl, cyano lower alkyl,lower alkyl thiol, alkoxycarbonyl lower alkyl, alkylthio lower alkyl,indolyl lower alkyl; aryl, optionally substituted with 1 to threesubstituents selected from the group of lower alkyl, hydroxy, (C₁-C₆)lower alkoxy, aryl lower alkoxy, halogen, —CF₃, —OCF₃, —OCHF₂, —OCH₂F—OCH₂CF₃, —OCF₂CF₃, —OCH₂CHF₂, alkylamido lower alkyl, dialkylamidolower alkyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl,—SCF₃, —SO₂[lower alkyl], sulfonyl cycloalkyl,

[0030] or (C₇-C₁₂) aryl lower alkyl, wherein the aryl moiety isoptionally substituted with halogen or alkoxy; with the proviso that R₁₁and R₁₂ can be taken together with the nitrogen to which they areattached to form an unsaturated heteroaromatic ring containing 2nitrogen atoms;

[0031] R₁₃ is selected from hydrogen, (C₁-C₆) lower alkyl, (C₇-C₁₂)lower aralkyl, or—(CH₂)_(p)—N(lower alkyl)₂;

[0032] R₁₄ and R₁₅ are, independently, selected from hydrogen, (C₁-C₆)lower alkyl, or (C₇-C₁₂) aryl lower alkyl, with the proviso that R₁₄ andR₁₅ can be taken together with the nitrogen atom to which they areattached to form a 5 to 7 membered saturated heterocycle, optionallycontaining one additional O or S atom (all of the above rings beingoptionally substituted with 1 or more alkyl groups); or a 5-memberedunsaturated heterocycle containing 1 to 3 nitrogen atoms;

[0033] R₁₆ and R₁₇ are, independently selected from the group ofhydrogen, (C₁-C₆) lower alkyl, [(C₁-C₆) lower alkyl]₂, (C₇-C₁₂) aryllower alkyl, lower alkoxy carbonyl, aryl lower alkoxy carbonyl, —CONH₂,—CONH [(C₁-C₆) lower alkyl], —CON [(C₁-C₆) lower alkyl]₂;cycloalkylamino (C₁-C₆) lower alkyl, [(C₁-C₆) lower alkyl]₂ amino; withthe proviso that R₁₆ and R₁₇ can be joined to form a 5 to 6 memberedsaturated ring to provide a bicyclic system, optionally containing oneor more alkyl groups including, but not limited to,1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane;

[0034] R₁₈ is one to three substituents selected independently from thegroup of hydrogen, or (C₁-C₆) lower alkyl;

[0035] R₁₉ is selcted from the group of hydrogen, (C₁-C₆) lower alkyl,—N[(C₁-C₆) lower alkyl]₂, or cycloalkylamine when Y′=CH₂; or it isselected from the group of hydrogen and (C₁-C₆) lower alkyl when Y′=X′;

[0036] R₂₀ is selected from the group of hydrogen, (C₁-C₆) lower alkyl,(C₃-C₆) lower alkenyl, (C₃-C₆) lower alkynyl, (C₃-C₈) cycloalkyl,—CONH₂, —CON[lower alkyl]₂, carbonyl lower alkyl, lower alkyl CONH[loweralkyl], lower alkyl CON[lower alkyl]₂, cycloalkylamino carbonyl,cycloalkylamino carbonyl lower alkyl, arylamino carbonyl lower alkyl,lower alkoxy carbonyl, lower alkoxy carbonyl lower alkyl,—(CH₂)_(p)—N[lower alkyl]₂, —(CH₂)_(p)—N[lower alkenyl]₂, —CH[aryl]₂wherein the aryl is optionally substituted by (C₁-C₆) lower alkyl,C₁-C₆) lower alkoxy, or halogen;

[0037] benzodioxolyl, benzodioxolyl lower alkyl, benzodioxanyl,benzodioxanyl lower alkyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,furancarbonyl, —SO₂[Iower alkyl], aryl optionally substituted by one tothree substituents selected independently, from the group of hydrogen,halogen, (C₁-C₆) lower alkyl, (C₃-C₆) lower alkenyl, (C₃-C₆) loweralkynyl, lower alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F, —OCF₂CF₃,—OCH₂CHF₂, —CO lower alkyl, —CN, nitro, —SCH₃, aryl lower alkoxy, aryllower alkoxy carbonyl, indolyl, morpholino or thiomorpholino; or(C₇-C₁₂) lower aralkyl wherein the aryl moiety is optionally substitutedwith halogen, (C₁-C₆) lower alkyl, or (C₁-C₆) lower alkoxy;

[0038] R₂₁ and R₂₂ are selected, independently, from the group ofhydrogen, (C₁-C₆) lower alkyl, or (C₇-C₁₂) aryl lower alkyl;

[0039] R₂₃ is selected from hydrogen, or (C₁-C₆) lower alkyl;

[0040] R₂₄ is selected from the group of (C₁-C₆) lower alkyl, (C₇-C₁₂)aryl lower alkyl, lower alkoxycarbonyl, or SO₂[(C₁-C₆) lower alkyl];

[0041] R₂₅ is selected from (C₁-C₆) lower alkyl, (C₇-C₁₂) aryl loweralkyl, lower alkoxycarbonyl, aryl lower alkoxycarbonyl, —COOH, —CONH₂,—CONH[(C₁-C₆) lower alkyl], —CONH[(C₇-C₁₂) aryl lower alkyl],—CON[(C₁-C₆) lower alkyl]₂, or —CON[(C₇-C₁₂) aryl lower alkyl]₂;

[0042] R₂₆ is selected from hydrogen, lower alkoxycarbonyl,fluorenylalkoxycarbonyl, aryl lower alkyl, or aryl lower alkoxycarbonyl;

[0043] R₂₇ and R₂₈ are, independently, selected from the group ofhydrogen, lower alkyl, aryl lower alkyl (the aryl moiety beingoptionally substituted by hydroxy, alkoxy, or halogen), or

[0044] with the proviso that R₂₇ and R₂₈ can be taken together with thecarbon to which they are attached to form a 3 to 6-membered saturatedring;

[0045] R₂₉ and R₃₀ are, independently, selected from the group ofhydrogen, (C₁-C₆) lower alkyl, (C₃-C₆) lower alkenyl, (C₃-C₆) loweralkynyl, cyclo lower alkyl, or aryl [optionally substituted by hydroxy,(C₁-C₆) lower alkoxy, (C₁-C₆) lower alkyl, halo, cyano, —SO₂[(C₁-C₆)lower alkyl, or —S[(C₁-C₆) lower alkyl];

[0046] R₃₁ is selected from the group of hydroxy, (C₁-C₆) lower alkoxy,aryl lower alkoxy, amino, —NH[(C₁-C₆) lower alkyl], or —N[(C₁-C₆) loweralkyl]₂;

[0047] R₃₂ is selected from the group of hydrogen, or (C₁-C₆) loweralkyl;

[0048] R₃₃ is one to three substituents selected from the group ofhydrogen, or (C₁-C₆) lower alkyl;

[0049] R₃₄ and R₃₅ are, independently, selected from the group ofhydrogen, (C₁-C₆) lower alkyl, (C₇-C₁₂) aryl lower alkyl, with theproviso that R₃₄ and R₃₅ taken together with the nitrogen atom to whichthey are attached, may form a 4 to 8 membered saturated heterocycle,optionally containing one additional O, S or N[(C₁-C₆) lower alkyl], allthe above rings being optionally substituted with 1 or more alkylgroups; or a 5 membered unsaturated heterocycle containing 2 to 3nitrogen atoms;

[0050] R₃₆ is selected from the group of hydrogen, or (C₁-C₆) loweralkyl;

[0051] X′ is O, S, SO, SO₂;

[0052] Y′=CH₂ or X′;

[0053] K=Y′ or N[(C₁-C₆) lower alkyl];

[0054] m is an integer from 1 to 4;

[0055] n is an integer from 1 to 4;

[0056] p is an integer from 2 to 4;

[0057] q is an integer from 1 to 5;

[0058] r is an integer from 1 to 2;

[0059] s is an integer from 0 to 1;

[0060] and the pharmaceutically acceptable salts, or pro-drug formsthereof.

[0061] Among the preferred compounds of this invention are those of theformula:

[0062] wherein:

[0063] R₁ and R₂ are, independently, selected from hydrogen,(C₁-C₆)lower alkyl, halogen, cyano, trifluoromethyl, hydroxy, amino,(C₁-C₆) lower alkylamino, (C₁-C₆) lower alkoxy, —OCF₃, (C₁-C₆) loweralkoxy carbonyl, —NHCO[(C₁-C₆)lower alkyl], carboxy, —CONH₂,—CONH[(C₁-C₆) lower alkyl], or —CON[(C₁-C₆) lower alkyl]₂;

[0064] R₃ is a substituent selected from hydrogen, (C₁-C₆) lower alkyl,(C₁-C₆) lower alkoxy, hydroxy, amino, (C₁-C₆) lower alkylamino, —COlower alkyl (C₁-C₆), or halogen;

[0065] R₄ consists of the moiety B-C; wherein:

[0066] B is selected from the group of:

[0067] and C is selected from the group of:

[0068] wherein:

[0069] A is CH or N;

[0070] R₅, R₆, R₇, R₈, R₉, R₁₀ are independently selected from hydrogen,(C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy, (C₁-C₆) lower alkyl carbonyl,(C₃-C₆) lower alkenyl, (C₃-C₆) lower alkynyl, hydroxy (C₁-C₆) loweralkyl, alkoxy(C₁-C₆) lower alkyl, acyloxy(C₁-C₆) lower alkyl, (C₃-C₈)cycloalkyl, formyl, cycloalkylcarbonyl, carboxy, lower alkoxy carbonyl,cycloalkyloxycarbonyl, carbamoyl, —O—CH₂—CH═CH₂, halogen, halo loweralkyl, trifluoromethyl, —OCF₃, —S[(C₁-C₆) lower alkyl], —OC(O)N[(C₁-C₆)lower alkyl]₂, —CONH[(C₁-C₆) lower alkyl], —CON[(C₁-C₆) lower alkyl]₂,(C₁-C₆) lower alkylamino, di-[(C₁-C₆) lower alkyl]amino, (C₁-C₆) loweralkyl di-[(C₁-C₆) lower alkyl]amino, hydroxy, cyano,trifluoromethylthio, nitro, amino, (C₁-C₆) lower alkylsulfonyl,aminosulfonyl, or (C₁-C₆) lower alkylaminosulfonyl;

[0071] R₂₉ and R₃₀ are, independently, selected from the group of H,C₁-C₆ alkyl, (C₃-C₆) lower alkenyl, C₃-C₆ alkynyl, or cyclo C₃-C₆ alkyl;

[0072] R is selected from lower alkyl, —NHNH₂, —NHOR₃₁; or—CH═CH—N[R₃₂]₂; lower alkoxy; phenyl optionally substituted by from oneto three substituents selected from (C₁-C₆) lower alkyl or halogen; or amoiety of the formulae:

[0073] R₁₁ and R₁₂ are, independently, selected from hydrogen, (C₁-C₆)lower alkyl, (C₃-C₆) lower alkenyl, (C₃-C₈) cycloalkyl optionally mono-or di-[(C₁-C₆) loweralkyl] substituted, cycloalkyl lower alkyl, halolower alkyl, cyano lower alkyl, lower alkyl thiol, alkoxycarbonyl loweralkyl, or alkylthio lower alkyl; or a moiety of the formulae:

[0074] R₁₃ is selected from hydrogen, (C₁-C₆) lower alkyl, (C₇-C₁₂)lower aralkyl, or—(CH₂)_(p)—N(lower alkyl)₂;

[0075] R₁₄ and R₁₅ are, independently, selected from hydrogen, (C₁-C₆)lower alkyl, with the proviso that R₁₄ and R₁₅ can be taken togetherwith the nitrogen atom to which they are attached to form:

[0076] a) a 5 to 7 membered saturated heterocycle, optionallysubstituted with 1 or more alkyl groups; or

[0077] b) a 5-membered unsaturated heterocycle containing 1 to 3nitrogen atoms;

[0078] R₁₈ is one to three substituents selected independently from thegroup of hydrogen, or (C₁-C₆) lower alkyl;

[0079] R₁₉ is selcted from the group of hydrogen, (C₁-C₆) lower alkyl,—N[(C₁-C₆) lower alkyl]₂, or cycloakylamine when Y′=CH₂; or it isselected from the group of hydrogen and (C₁-C₆) lower alkyl when Y′=X′;

[0080] R₂₀ is selected from the group of hydrogen, (C₁-C₆) lower alkyl,(C₃-C₆) lower alkenyl, (C₃-C₆) lower alkynyl, (C₃-C₈) cycloalkyl,—CONH₂, —CON[lower alkyl]₂, carbonyl lower alkyl, lower alkyl CONH[loweralkyl], lower alkyl CON[lower alkyl]₂, lower alkoxy carbonyl,(CH₂)_(p)—N[lower alkyl]₂, —(CH₂)r-N[lower alkenyl]₂, —CH[phenyl]₂wherein the phenyl ring is optionally substituted by (C₁-C₆) loweralkyl, C₁-C₆) lower alkoxy, or halogen; or R₂₀ is a moiety of theformula:

[0081] R₂₁ and R₂₂ are selected, independently, from the group ofhydrogen, (C₁-C₆) lower alkyl, or (C₇-C₁₂) aryl lower alkyl;

[0082] R₂₃ is selected from hydrogen, cyano or (C₁-C₆) lower alkyl;

[0083] R₂₄ is selected from the group of (C₁-C₆) lower alkyl, loweralkoxycarbonyl, or SO₂[(C₁-C₆) lower alkyl];

[0084] R₂₅ is selected from (C₁-C₆) lower alkyl, lower alkoxycarbonyl,—COOH, —CONH₂, —CONH[(C₁-C₆)lower alkyl)], or —CON[(C₁-C₆)loweralkyl)]₂;

[0085] R₂₆ is selected from hydrogen, lower alkoxycarbonyl, orfluorenylalkoxycarbonyl;

[0086] R₂₇ and R₂₈ are, independently, selected from the group ofhydrogen or lower alkyl; with the proviso that R₂₇ and R₂₈ can be takentogether with the carbon to which they are attached to form a 3 to6-membered saturated ring;

[0087] R₃₁ is selected from the group of hydroxy, (C₁-C₆) lower alkoxy,amino, —NH[(C₁-C₆) lower alkyl], or —N[(C₁-C₆) lower alkyl]₂;

[0088] R₃₂ is elected from the group of hydrogen, or (C₁-C₆) loweralkyl;

[0089] R₃₃ is one to three substituents selected from the group ofhydrogen, or (C₁-C₆) lower alkyl;

[0090] R₃₄ and R₃₅ are, independently, selected from the group ofhydrogen, or (C₁-C₆) lower alkyl, with the proviso that R₃₄ and R₃₅taken together with the nitrogen atom to which they are attached, mayform a 5 membered unsaturated heterocycle containing 2 to 3 nitrogenatoms;

[0091] X′ is O;

[0092] Y′=CH₂ or X′;

[0093] K=Y′ or N[(C₁-C₆) lower alkyl];

[0094] m is an integer from 1 to 4;

[0095] n is an integer from 1 to 4;

[0096] p is an integer from 2 to 4;

[0097] q is an integer from 1 to 5;

[0098] r is an integer from 1 to 2;

[0099] s is an integer from 0 to 1;

[0100] and the pharmaceutically acceptable salts, or pro-drug formsthereof.

[0101] Within each of the groups of compounds described herein is afurther subset of compounds having the general formula:

[0102] wherein R, R₁, R₂, R₃ and R₄ are as defined in the relevantgroup, or a pharmaceutically acceptable salt form thereof. A furthersubset of each of these groups includes those compounds wherein R₁, R₂and R₃ are each hydrogen and all other variables are as described in therelevant group, or a pharmaceutically acceptable salt thereof.

[0103] As used herein the term “lower” in relation to carbon chains,such as alkoxy, alkyl, alkynyl, alkenyl, etc., is understood to refer tothose groups having up to 6 carbon atoms. Halogen refers to fluorine,chlorine, bromine or iodine. Cycloalkyl, whether used separately or as apart of a combined moiety, refers to cycloalkyl groups from 3 to 8carbon atoms, preferably from 3 to 6 carbon atoms.

[0104] It is understood by those practicing the art that some of thecompounds of this invention depending on the definition of R₁, R₂, R₃,R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₂₉, and R₃₀ may contain one or moreasymmetric centers and may thus give rise to enantiomers anddiastereomers. The present invention includes all stereoisomersincluding individual diastereomers and resolved, enantiomerically pure Rand S stereoisomers; as well as racemates, and all other mixtures of theR and S stereoisomers and pharmaceutically acceptable salts thereof,which possess the indicated activity. Optical isomers may be obtained inpure form by standard procedures known to those skilled in the art. Itis also understood that this invention encompasses all possibleregioisomers, E/Z isomers, endo-exo isomers, and mixtures thereof whichpossess the indicated activity. Such isomers may be obtained in pureform by standard separation procedures known to those skilled in theart. It is understood also by those practicing the art that some of thecompounds of this invention depending on the definition of R₅, R₆, R₈,R₉, R₁₀, R₂₉ and R₃₀ may be chiral due to hindered rotation, and giverise to atropisomers which can be resolved and obtained in pure form bystandard procedures known to those skilled in the art. Also included inthe present invention are all polymorphs and hydrates of the compoundsof the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0105] The present invention comprises the compounds described above, aswell as pharmaceutical compositions containing the compounds of thisinvention in combination or association with one or morepharmaceutically acceptable carriers or excipients. In particular, thepresent invention provides a pharmaceutical composition which comprisesa therapeutically or pharmaceutically effective amount of one or morecompounds of this invention and a pharmaceutically acceptable carrier orexcipient.

[0106] This invention also comprises methods for treating conditions ina mammal, preferably a human, which are remedied or alleviated byoxytocin antagonist activity including, but not limited to, treatment orprevention of preterm labor, dysmenorrhea and suppressing labor prior tocaesarian delivery whenever desirable in a mammal, preferably in ahuman. The methods comprise administering to a mammal in need thereof apharmaceutically or therapeutically effective amount of one or more ofthe compounds of this invention.

[0107] The present invention also comprises combinations of thecompounds of the present invention with one or more agents useful in thetreatment of disorders such as preterm labor, dysmenorrhea, and stoppinglabor prior to caesarian delivery. More specifically, the compounds ofthe present invention may be effectively administered in combinationwith effective amounts of other tocolytic agents used in the treatmentor prevention of preterm labor, dysmenorrhea or suppressing labor priorto caesarean delivery including β-adrenergic agonists, calcium channelblockers, prostaglandin synthesis inhibitors, other oxytocin antagonists(e.g. atosiban), magnesium sulfate, ethanol, and other agents useful inthe treatment of said disorders. The present invention is to beunderstood as embracing all simultaneous or alternating treatments ofany combination of the compounds of the present invention with othertocolytic agents with any pharmaceutical composition useful for thetreatment of preterm labor, dysmenorrhea, and suppressing labor prior tocaesarean delivery in mammals.

[0108] The compositions are preferably adapted for intravenous (bothbolus and infusion) and oral administration. However, they may beadapted for other modes of administration including subcutaneous,intraperitoneal, or intramuscular administration to a human or a farmanimal in need of a tocolytic agent.

[0109] The compounds of the present invention can be used in the form ofsalts derived from non toxic pharmaceutically acceptable acids or bases.These salts include, but are not limited to, the following: salts withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid and, as the case may be, such organicacids as acetic acid, oxalic acid, citric acid, tartaric acid, succinicacid, maleic acic, benzoic acid, benzene sulfonic acid, fumaric acid,malic acid, methane sulfonic acid, pamoic acid, and para-toluen sulfonicacid . Other salts include salts with alkali metals or alkaline earthmetals, such as sodium, potassium, calcium or magnesium, or with organicbases including quaternary ammonium salts. The compounds can also beused in the form of esters, carbamates and other conventional prodrugforms, which in general, will be functional derivatives of the compoundsof this invention which are readily converted to the active moiety invivo. This is meant to include the treatment of the various conditionsdescribed hereinbefore with a compound of this invention or with acompound which is not specifically disclosed but which converts to acompound of this invention in vivo upon administration. Also includedare metabolites of the compounds of the present invention defined asactive species produced upon introduction of these compounds into abiological system.

[0110] When the compounds of this invention are employed for the aboveutilities, they may be combined with one or more pharmaceuticallyacceptable excipients or carriers, for example, solvents, diluents andthe like, and may be administered orally in such forms as tablets,capsules (including time release and sustained release formulations),pills, dispersible powders, granules, or suspensions containing, forexample, from 0.05 to 5% of suspending agent, syrups containing, forexample, from about 10 to 50% of sugar, and elixirs and the like, orparenterally in the form of sterile injectable solutions, suspensions oremulsions containing from about 0.05 to 5% suspending agent in anisotonic medium. Such pharmaceutical preparations may contain, forexample, from about 25 to about 90% of the active ingredient incombination with the carrier, more usually between about 5% and 60% byweight.

[0111] The effective dosage of active ingredients employed may varydepending on the particular compound or salt employed, the mode ofadministration, age, weight, sex and medical condition of the patient,and the severity of the condition being treated. An ordinarily skilledphysician, veterinarian or clinician can readily determine and prescribethe effective amount of the agent required to prevent, counter or arrestthe progress of the condition. However, in general, satisfactory resultsare obtained when the compounds of the invention are administered at adaily dose of from about 0.5 to about 500 mg/Kg of mammal body weight,preferably given in divided doses two to four times a day, or in asustained release form. For most large mammals the total daily dosage isfrom about 0.5 to 100 mg, preferably from 0.5 to 80 mg/Kg. Dosage formssuitable for internal use comprise from about 0.05 to 500 mg of theactive compound in intimate admixture with a solid or liquidpharmaceutically acceptable carrier. This dosage re.g.imen may beadjusted to provide the optimal therapeutic response. For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation.

[0112] These active compounds may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, glycerol, non-ionic surfactants and edibleoils such as corn, peanut and sesame oils, as are appropriate to thenature of the active ingredient and the particular form ofadministration desired. Adjuvants customarily employed in thepreparation of pharmaceutical compositions may be advantageouslyincluded, such as flavoring agents, coloring agents, preserving agents,and antioxidants, for example vitamin E, ascorbic acid, BHT and BHA.

[0113] These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

[0114] The pharmaceutical forms suitable for injectable use includesterile aqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy injectability exists. It must be stable underconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol (e.g. glycerol, propylene glycol, and liquid polyethyleneglycol), suitable mixtures thereof, and vegetable oil.

[0115] Furthermore, active compounds of the present invention can beadministered intranasally using vehicles suitable for intranasaldelivery, or transdermally using transdermal skin patches known to thoseordinarily skilled in the art. When using a transdermal delivery system,the dosage administration will be continuous rather than in a single ordivided daily doses. The compounds of the present invention can also beadministered in the form of liposome delivery system wherein theliposomal lipid bilayers are formed from a variety of phospholipids.

[0116] Compounds of the present invention may also be delivered by theuse of carriers such as monoclonal antibodies to which the activecompounds are coupled. The compounds of the present invention may alsobe coupled to soluble polymers as drug carriers or to biode.g.radablepolymers useful in achieving controlled release of the active agent.

[0117] Also according to the present invention there are providedprocesses for producing the compounds of the present invention.

[0118] Process of the Invention

The compounds of the present invention may be prepared according to oneof the general processes outlined below.

[0119] The compounds of general formula (I) wherein R₄ consists of themoiety B-C, where B is selected from the group (a) or (b) and C isselected from the group of (c), (d), (e) and (f) defined hereinbefore,can be conveniently prepared as shown in Scheme I.

[0120] According to the above preferred process, a tricyclic diazepineof formula (1) wherein

[0121] R₃ and R₄ are defined hereinbefore, is reacted withperhaloalkanoyl halide preferably trichloroacetyl chloride in thepresence of an organic base such as N,N-diisopropylethyl amine (Hunig'sbase) in an aprotic organic solvent such as dichloromethane attemperatures ranging from −10° C. to ambient to provide the desiredtrichloroacetyl intermediate of formula (2). Subsequent hydrolysis of(2) with aqueous base such as sodium hydroxide in an organic solventsuch as tetrahydrofuran or acetone at temperatures ranging from −10° C.to ambient, yields the intermediate acid of formula (3). The requiredactivation of the carboxylic acid (3) for the subsequent coupling with aprimary or secondary amine, hydroxylamine or hydrazine of formula (5)can be accomplished in several ways. Thus, (3) can be converted to anacid halide preferably a chloride or bromide of formula (4, J=COCl orCOBr) by reaction with thionyl chloride(bromide) or oxalylchloride(bromide) or similar reagents known in the art, either neat orin the presence of an inorganic base such as potassium carbonate, or inthe presence of an organic base such as pyridine,4-(dimethylamino)pyridine, or a tertiary amine such as triethylamine inan aprotic solvent such as dichloromethane, N,N-dimethylformamide ortetrahydrofuran at temperatures ranging from −5° C. to 50° C. to yieldthe intermediate acylated derivative (4). Subsequent coupling of theacid chloride(bromide) (4, J=COCl or COBr) with an appropriatelysubstituted primary or secondary amine, hydroxylamine or hydrazine offormula (5) in the presence of a stoichiometric amount of Hujnig's basein an aprotic solvent such as dichloromethane, N,N-dimethylformamide ortetrahydrofuran at temperatures ranging from ambient to the refluxtemperature of the solvent provides the desired compounds of formula (I)wherein

[0122] R, R₃ and R₄ are as defined hereinbefore.

[0123] Alternatively, the acylating species can be a mixed anhydride ofthe corresponding carboxylic acid, such as that prepared by treatingsaid acid of formula (3) with 2,4,6-trichlorobenzoyl chloride in anaprotic organic solvent such as dichloromethane according to theprocedure of Inanaga et al., Bull. Chem. Soc. Jpn. 52, 1989 (1979).Treatment of said mixed anhydride of formula (4) with an appropriatelysubstituted primary or secondary amine, hydroxylamine or hydrazine offormula (5) in an aprotic solvent such as dichloromethane, attemperatures ranging from ambient to the reflux temperature of thesolvent provides the desired compounds of formula (I) wherein

[0124] R, R₃ and R₄ are as defined hereinbefore.

[0125] Alternatively, amidation of the carboxylic acids of formula (3)can be effectively carried out by treatment of said acid withtriphosgene in an aprotic solvent such as dichloromethane followed byreaction of the activated intermediate with an appropriately substitutedprimary or secondary amine, hydroxylamine or hydrazine of formula (5) inthe presence of an organic base such as Hunig's base at temperaturesranging from −10° C. to ambient.

[0126] Another preferred process for the preparation of the compounds ofthe present invention of formula (I) wherein

[0127] R, R₃ and R₄ are as defined hereinbefore, consists of treatingthe acid of formula (3) with an activating reagent such asN,N-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride in the presence of 1-hydroxybenzotriazolefollowed by reaction of the activated intermediate with an appropriatelysubstituted primary or secondary amine, hydroxylamine or hydrazine offormula (5), preferably in the presence of an organic base such asHünig's base and a catalytic amount of 4-(dimethylamino)pyridine, in anaprotic solvent such as dichloromethane, N,N-dimethylformamide ortetrahydrofuran, at temperatures ranging from −10° C. to ambient.

[0128] In another preferred process, said acid (3) can be activated bytreatment with other activating agents such as N,N′carbonyldiimidazole,in an aprotic solvent such as dichloromethane or tetrahydrofuran, attemperatures ranging from −10° C. to the reflux temperature of thesolvent. Subsequent reaction of the intermediate activated imidazolidewith an appropriately substituted primary or secondary amine,hydroxylamine or hydrazine of formula (5) provides the desired compoundsof formula (I) wherein

[0129] R, R₃ and R₄ are as defined hereinbefore.

[0130] Alternatively, the coupling of the appropriately substitutedprimary or secondary amine of formula (5) with said acid of formula (3)can be effectively carried out by using hydroxybenzotriazoletetramethyluronium hexafluorophosphate as the coupling reagent in thepresence of an organic base such as Hunig's base, and in a solvent suchas N,N-dimethylformamide, at temperatures ranging from −10° C. toambient to provide in good isolated yield and purity the desiredcompounds of formula (I) wherein

[0131] R, R₃ and R₄ are as defined hereinbefore.

[0132] Related coupling reagents such as diphenylphosphoryl azide,diethyl cyano phosphonate, benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate and all other reagents known in theliterature that have been used in the formation of amide bonds inpeptide synthesis can also be used for the preparation of compounds offormula (I) wherein

[0133] R, R₃ and R₄ are as defined hereinbefore.

[0134] As an alternative, reaction of the intermediate3-trihalomethylketone of formula (2) directly with an appropriatelysubstituted primary or secondary amine, hydroxylamine or hydrazine offormula (5) also provides the desired compounds of formula (I) wherein

[0135] R, R₃ and R₄ are as defined hereinbefore.

[0136] The method of choice for the preparation of compounds of formula(I) from the intermediate carboxylic acid (3) is ultimately chosen onthe basis of its compatibility with the R, R₃ and R₄ groups, and itsreactivity with the tricyclic diazepine of formula (1).

[0137] Another preferred process for the preparation of (I) of Scheme Iis shown in Scheme II. A tricyclic diazepine of formula (1) is reactedwith diphosgene in an aprotic solvent such as dichloromethane preferablyin the presence of an organic base such as triethylamine, followed byreaction of the resulting acylated intermediate with an appropriatelysubstituted primary or secondary amine, hydroxylamine or hydrazine offormula (5) to provide the desired compounds of formula (I) wherein

[0138] R, R₃and R₄ are as defined hereinbefore.

[0139] The tricyclic diazepines of formula (I) of Scheme (I) wherein R₄is defined hereinbefore, can be conveniently prepared as shown in SchemeIII.

[0140] Thus, a tricyclic diazepine of formula (6) is treated with anappropriately substituted acylating agent such as an aroyl halide,preferably an appropriately substituted acyl chloride (or bromide) offormula (7, J=COCl or COBr) wherein R₄ is ultimately chosen on the basisof its compatibility with the present reaction scheme, in the presenceof an inorganic base such as potassium carbonate, or in the presence ofan organic base such as pyridine, 4-(dimethylamino)pyridine, or atertiary amine such as triethylamine or N,N-diisopropylethyl amine, inan aprotic solvent such as dichloromethane, N, N-dimethiylformamide ortetrahydrofuran, at temperatures ranging from −5° C. to 50° C. toprovide intermediates of general formula (I) wherein R₄ is definedhereinbefore.

[0141] Alternatively, the acylating species of formula (7) can be amixed anhydride of the corresponding carboxylic acid, such as thatprepared by treating said acid with 2,4,6-trichlorobenzoyl chloride inan aprotic organic solvent such as dichloromethane according to theprocedure of Inanaga et al., Bull. Chem. Soc. Jpn., 52, 1989 (1979).Treatment of said mixed anhydride of general formula (7) with atricyclic diazepine of formula (6) in a solvent such as dichloromethaneand in the presence of an organic base such as 4-(dimethylamino)pyridineat temperatures ranging from 0° C. to the reflux temperature of thesolvent, yields the intermediate acylated derivative (1) of Scheme III.

[0142] The acylating intermediate of formula (7) is ultimately chosen onthe basis of its compatibility with the R₄ groups, and its reactivitywith the tricyclic diazepine of formula (6).

[0143] The desired intermediates of formula (7) of Scheme IlIl whereinR₄ consists of the moiety B-C wherein B is (a) and C is (c) can beconveniently prepared by a process shown in Scheme IV. Thus, anappropriately substituted aryl(heteroaryl) iodide (bromide, chloride, ortrifluoromethane sulfonate) of formula (8, wherein P is a carboxylicacid protecting group, preferably P=alkyl or benzyl, M=I, Br, Cl, OTf),and A, R₅, R₆ and R₇ are defined hereinbefore, is reacted with anaryl(heteroaryl) tri(alkyl)tin(IV) derivative of formula (9,W=Sn(trialkyl)₃, preferably Sn(n-Bu)₃) wherein A, R₈, R₉ and R₁₀ aredefined hereinbefore, in the presence of a Pd(0) catalyst in thepresence or absence of inorganic salts (e.g. LiCl), to provide theintermediate ester (10). Subsequent unmasking of the carboxylic acid byhydrolysis, hydrogenolysis or similar methods known in the art, followedby activation of the intermediate acid (II) provides the desiredintermediates of formula (19) wherein A, R₅, R₆, R₇, R₈, R₉ and R₁₀ arehereinbefore defined, suitable for coupling with the tricyclic diazepineof formula (6).

[0144] The desired intermediates of formula (7) of Scheme III wherein R₄consists of the moiety B-C where B is (a) and C is (d), (e) or (f) or Bis (b) and C is either (c), (d), (e) or (f) can be prepared by a processanalogous to that exemplified in Scheme IV by replacing intermediates offormula (8 and 9) with appropriately substituted naphthyl, quinolyl,pyrimidinyl or pyrazinyl intermediates.

[0145] Alternatively, the desired intermediates of formula (10) ofScheme IV wherein R₄ consists of the moiety B-C where B is (a) and C is(c) can be prepared by coupling of the iodide(bromide, chloride,trifluoromethanesulfonate) (8, M=I, Br, Cl, or OTf) with anappropriately substituted aryl(heteroaryl) boron derivative of formula(9, preferably W=B(OH)₂) in the presence of a palladium catalyst such aspalladium(II) acetate or tetrakis(triphenylphosphine) palladium(0) andan organic base such as triethylamine or an inorganic base such assodium(potassium or cesium) carbonate with or without addedtetrabutylammonium bromide(iodide), in a mixture of solvents such astoluene-ethanol-water, acetone-water, water or water-acetonitrile attemperatures ranging from ambient to the reflux temperature of thesolvent (Suzuki, Pure& Appl. Chem. 66, 213-222 (1994), Badone et al., J.Org. Chem. 62, 7170-7173 (1997); Wolfe et al. J. Am. Chem. Soc. 121,9559 (1999); Shen, Tetr. Letters 38, 5575 (1997)). The exact conditionsfor the Suzuki coupling of the halide and the boronic acid intermediatesare chosen on the basis of the nature of the substrate and thesubstituents. Alternatively, the coupling of (8, M=I or Br) with (9,A=N) can be carried out by using a dialkylborane, preferably adiethylpyridoborane in the presence of an inorganic base such aspotassium hydroxide and tetrabutylammonium bromide(iodide) in an aproticsolvent such as tetrahydrofuran, according to the method of Ishikura etal., Synthesis 936-938 (1984). The desired intermediates of formula (10)of Scheme IV can be similarly prepared from the bromide (8, M=Br) andthe boronic acid (9) in a solvent such as dioxane, in the presence ofpotassium phosphate and a Pd(0) catalyst.

[0146] Alternatively, a cross coupling reaction of an iodide (bromide,or trifluoromethanesulfonate) of formula (9, W=Br, I, OTf) with abis(pinacolato)diboron [boronic acid, or trialkyl tin(IV)] derivative offormula (8, M=

[0147] B(OH)₂, or SnBu₃) yields the desired intermediate of formula (10)which is converted to (I) in the manner of Scheme IV.

[0148] The desired intermediates of formula (10) of Scheme IV wherein R₄consists of the moiety B-C wherein B is (a) and C is (d), (e) or (f), orB is (b) and C is either (c), (d), (e) or (f), can be prepared inanalogous fashion by replacing intermediates of formulas (8 and 9) withappropriately substituted naphthyl, quinolyl, pyrimidinyl or pyrazinylintermediates.

[0149] The required appropriately substituted aryl(heteroaryl) halidesof formula (8, M=Br or I) of Scheme IV are either availablecommercially, or are known in the art or can be readily accessed inquantitative yields and high purity by diazotization of thecorresponding substituted anilines (8, P=H, alkyl or benzyl, M=NH₂)followed by reaction of the intermediate diazonium salt with iodine andpotassium iodide in aqueous acidic medium essentially according to theprocedures of Street et al,. J. Med. Chem. 36, 1529 (1993) and Coffen etal., J. Org. Chem. 49, 296 (1984) or with copper(I) bromide,respectively (March, Advanced Organic Chemistry, 3^(rd) Edn., p.647-648,John Wiley & Sons, New York (1985)).

[0150] Alternatively, the desired intermediates of formula (11, A=CH) ofScheme IV wherein R₄ consists of the moiety B-C wherein B is (a, A=CH)and C is (c, A=CH) can be conveniently prepared as shown in Scheme V bycross-coupling reaction of an appropriately substituted pinacolatoborane of formula (13, A=CH) wherein R₈, R₉ and R₁₀ are hereinbeforedefined, with an aryl triflate of formula (14, Y=OTf) or an aryl halide(14, Y=Br, I) wherein R₅, R₆ and R₇ are defined hereinbefore, accordingto the general procedures of Ishiyama et al., Tetr. Lett. 38, 3447-3450(1997) and Giroux et al. Tetr. Lett. 38, 3841-3844 (1997), followed bybasic or acidic hydrolysis of the intermediate nitrile of formula (15)(cf. March, Advanced Organic Chemistry, 3rd Edn., John Wiley & Sons, NewYork, p. 788 (1985)).

[0151] Alternatively, reaction of an iodide (bromide, chloride, ortrifluoromethanesulfonate) of formula (12, X=Br, C1,1, or OTf) with abis(pinacolato)diboron [boronic acid or trialkyl tin(IV)] derivative offormula (14, Y=

[0152] B(OH)₂, or SnBu₃) yields the desired intermediate of formula (15)which is converted to (11) in the manner of Scheme V.

[0153] The desired intermediates of formula (11) of Scheme IV can beprepared in analogous fashion by replacing intermediates of formulas (13and 14) with appropriately substituted naphthyl intermediates.

[0154] The desired phenyl boronic esters of formula (13) of Scheme V canbe conveniently prepared by the palladium-catalyzed cross-couplingreaction of the pinacol ester of diboronic acid (16) with anappropriately substituted aryl halide preferably a bromide or iodide(12, X=Br, I) or aryl triflate (12, X=OTf) according to the describedprocedures of Ishiyama et al., J. Org. Chem. 60, 7508-7510 (1995) andGiroux et al., Tetr. Lett. 38, 3841-3844 (1997).

[0155] The desired compounds of formula (1) of Scheme IV wherein R₄consists of the moiety B-C wherein B is (a) and C is (c) can bealternatively prepared by a process shown in Scheme VI.

[0156] Thus, a tricyclic diazepine of formula (6) is treated with anappropriately substituted acylating agent such as a haloaroyl(heteroaroyl)halide, preferably an iodo(bromo) aroyl(heteroaroyl)chloride(bromide) of formula (17, J=COCl or COBr; X=I, Br) wherein A,R₅, R₆ and R₇ are hereinbefore defined using any of the procedureshereinbefore described, to provide the acylated intermediate of generalformula (18) of Scheme VI.

[0157] Alternatively, the acylating species of formula (17) can be amixed anhydride of the corresponding carboxylic acid. Treatment of saidmixed anhydride of general formula (17) with a tricyclic diazepine offormula (6) according to the procedure described hereinbefore yields theintermediate acylated derivative (18).

[0158] The acylating intermediate of formula (17) is ultimately chosenon the basis of its compatibility with A and the R₅, R₆ and R₇ groups,and its reactivity with the tricyclic diazepine of formula (6).

[0159] A Stille coupling reaction of (18, X=I) with an appropriatelysubstituted organotin reagent such as a trialkyltin(IV) derivative,preferably a tri-n-butyltin(IV) derivative of formula (9, W=SnBu₃) whereA, R₈, R₉ and R₁₀ are hereinbefore defined, in the presence of acatalyst such as tetrakis (triphenylphosphine) palladium (0) in anaprotic organic solvent such as toluene and N,N-dimethylformamide, attemperatures ranging from ambient to 150° C. (cf. Farina et al., J. Org.Chem, 59, 5905 (1994) and references cited therein) affords the desiredcompounds of formula (1) wherein

[0160] A, R₃, R₅, R₆, R₇, R₈, R₉ and R₁₀ are as defined hereinbefore.

[0161] Alternatively, the reaction of a compound of formula (18, X=Cl,Br or I) with an appropriately substituted aryl(heteroaryl) boronic acidof formula (9, W=B(OH)₂) wherein A, R₅, R₆, R₇, R₈, R₉ and R₁₀ arehereinbefore defined, in a mixture of solvents such astoluene-ethanol-water, and in the presence of a Pd(0) catalyst and abase such as sodium carbonate, at temperatures ranging from ambient tothe reflux temperature of the solvent, yields the desired compounds offormula (1) wherein

[0162] A, R₃, R₅, R₆, R₇, R₈, R₉ and R₁₀ are as defined hereinbefore.

[0163] The preferred substituted aroyl(heteroaroyl) chlorides(bromides)of formula (17) of Scheme VI (X=I, Br; J=COCl or COBr) wherein A, R₅, R₆and R₇ are as defined hereinbefore, are either available commercially,or are known in the art, or can be readily prepared by proceduresanalogous to those in the literature for the known compounds.

[0164] The intermediates of formula (9, W=Sn(alkyl)₃, alkyl=n-butyl) ofScheme VI are either commercially available, or can be convenientlyprepared as shown in Scheme VII from the corresponding bromo startingmaterials of formula (20) wherein A, R₈, R₉, and R₁₀ are hereinbeforedefined, by first reacting them with n-butyl lithium followed byreaction of the intermediate lithiated species with a trialkyl(preferably trimethyl or tri-n-butyl) tin(IV) chloride.

[0165] The preferred substituted aryl(heteroaryl) boronic acids offormula (9, W=B(OH)₂) are either available commercially, or are known inthe art, or can be readily prepared by procedures analogous to those inthe literature for the known compounds.

[0166] The desired compounds of formula (1) of Scheme VI wherein R₄consists of the moiety B-C wherein B is (a) and C is (d), (e) or (f), orB is (b) and C is either (c), (d), (e) or (f) can be prepared inanalogous fashion by replacing intermediates of formulas (17 and 9) withappropriately substituted naphthyl, quinolyl, pyrimidinyl or pyrazinylintermediates.

[0167] Alternatively, as shown in Scheme Vil, the appropriatelysubstituted aroyl(heteroaroyl) halides, preferably aroyl(heteroaroyl)chlorides of formula (21, J=COCl) where A, R₅, R₆ and R₇ arehereinbefore defined, are reacted with a tricyclic diazepine of formula(6) to provide the intermediate bromides of formula (22). Subsequentreaction of (22) with an hexa alkyl-di-tin (preferablyhexa-n-butyl-di-tin(IV)) in the presence of a Pd(0) catalyst such astetrakis(tri-phenylphosphine)palladium(0) and lithium chloride, providesthe stannane intermediate of formula (23). Further reaction of thetri-n-butyl tin(IV) derivative (23) with the appropriately substitutedaryl(heteroaryl) halide of formula (24, M =bromo or iodo) wherein A, R₈,R₉, and R₁₀ are hereinbefore defined, in the presence of a Pd(0)catalyst such as tetrakis(triphenylphosphine) palladium(0), yields thedesired compounds of formula (1) wherein R₄ consists of the moiety B-Cwherein B is (a) and C is (c), and

[0168] A, R₅, R₆, R₇, R₈, R₉ and R₁₀ are defined hereinbefore.

[0169] The desired compounds of formula (1) of Scheme VII wherein R₄consists of the moiety B-C wherein B is (a) or (b) and C is (d), (e) or(f) can be prepared in analogous fashion by replacing intermediates offormulas (21 and 24) with appropriately substituted naphthyl, quinolyl,pyrimidinyl or pyrazinyl intermediates.

[0170] Alternatively, the desired compounds of formula (1) of SchemeVIII wherein R₄ consists of the moiety B-C wherein B is (a, A=CH), and Cis (c, A=CH) can be prepared as shown in Scheme IX.

[0171] Thus, an appropriately substituted biphenyl of formula (43)wherein R₅, R₆, R₇, R₈, R₉ and R₁₀ are defined hereinbefore, is treatedwith carbon monoxide in the presence of a tricyclic diazepine of formula(6), a palladium(0) catalyst preferably PdBr₂(Ph₃P)₂ and a tertiaryamine preferably n-tributylamine, in a solvent such as anisole ordioxane at temperatures ranging from ambient to the reflux temperatureof the solvent (cf. Schoenberg et al., J. Org. Chem. 39, 3327 (1974)) toprovide the desired compounds of formula (1) wherein A is CH, and

[0172] R₃, R₅, R₆, R₇, R₈, R₉ and R₁₀ are defined hereinbefore.

[0173] In analogous fashion one can prepare compounds of formula (1) ofScheme IX wherein R₄ consists of the moiety B-C wherein B is (b) and Cis (c, A=CH) or (d, A=CH) provided that the intermediates of formula(43) are replaced by the appropriately substituted phenyl or naphthylintermediates.

[0174] A preferred process for the preparation of the compounds offormula (1) of Scheme I wherein

[0175] A, R₃, R₅, R₆ and R₇ are defined hereinbefore, R₄ consists of themoiety B-C wherein B is (a) and C is (g) defined hereinbefore, is shownin Scheme X.

[0176] Thus, an appropriately substituted aroyl(heteroaroyl) halidepreferably an aroyl(heteroaroyl) chloride, of formula (25, J=COCl) isreacted with a tricyclic diazepine of formula (6) in the presence of abase such as pyridine, or a tertiary amine such as triethylamine orN,N-diisopropylethyl amine, in an aprotic organic solvent such asdichloromethane or tetrahydrofuran, at temperatures from −40° C. to 50°C. to provide the acylated intermediate of formula (26). Alternatively,the acylating species can be a mixed anhydride under the reactionconditions described hereinbefore. Subsequent reduction of (26) ispreferably effected under conditions of catalytic reduction (i.e.hydrogen, Pd on charcoal), transfer hydrogenation (i.e.hydrazine/ethanol/Pd on charcoal) or under chemical reduction conditions(i.e. with tin(lI)chloride dihydrate in a protic organic solvent such asethanol, or zinc in acetic acid) or related reduction conditions knownin the art, to yield the desired aniline of formula (27). The exactconditions for the conversion of the nitro to amino group are chosen onthe basis of compatibility with the preservation of other functionalgroups in the molecule. Condensation of (27) with a 1,4-diketone offormula (28) in an aprotic organic solvent such as benzene or toluene inthe presence of acetic acid or a catalytic amount of p-toluene sulfonicacid with concomitant removal of water at temperatures ranging fromambient to reflux temperature of the solvent according to the generalprocedure of Bruekelman et al., J. Chem. Soc. Perkin Trans. I, 2801-2807(1984), provides the desired compounds of formula (1) wherein R consistsof the moiety B-C wherein B is (a) and C is (9), and

[0177] A, R₃, R₅, R₆, R₇, R₂₉ and R₃₀ are defined hereinbefore.

[0178] The desired compounds of formula (1) of Scheme X wherein R₄consists of the moiety B-C wherein B is (b) and C is (g) can be preparedin analogous fashion by replacing the intermediate of formula (25) withan appropriately substituted naphthyl.

[0179] Alternatively, the desired compounds of formula (1) of Scheme Xcan be prepared as shown in Scheme XI.

[0180] According to this process an aryl(heteroaryl) nitrile of formula(29) is condensed with a 1,4-diketone of formula (28) in an aproticorganic solvent such as benzene or toluene, in the presence of aceticacid or a catalytic amount of p-toluenesulfonic acid with concomitantremoval of water, at temperatures ranging from ambient to refluxtemperature of the solvent according to the general procedure ofBruekelman et al., J. Chem. Soc. Perkin Trans. 1, 2801-2807 (1984), toyield the intermediate pyrrole of formula (30). Subsequent hydrolysis ofthe nitrile (30) to the carboxylic acid of formula (31) is efficientlyaccomplished by treatment of (30) with aqueous base (cf. March, AdvancedOrganic Chemistry, 3^(rd) Edn., John Wiley & Sons, New York, p. 788(1985)). Subsequent conversion of the acid (31) into an acylatingspecies, preferably an acid chloride(bromide) of formula (32, J=COCl orCOBr) or a mixed anhydride is accomplished by procedures analogous tothose described hereinbefore. The acylating agent (32) is used toacylate a tricyclic diazepine of formula (6) to provide the desiredcompounds of formula (1) wherein

[0181] and R₃ are defined hereinbefore, and R₄ consists of the moietyB-C wherein B is (a) and C is the moiety (g) defined hereinbefore.

[0182] The compounds of formula (1) of Scheme XI wherein R₄ consists ofthe moiety B-C wherein B is (b) and C is (g) defined hereinbefore can beprepared in analogous fashion by replacing the intermediates of formula(29) with an appropriately substituted naphthyl.

[0183] A preferred process for the preparation of the desired compoundsof general formula (I) of Scheme I wherein R₄ consists of the moietyB-C, where B is selected from the group (a) and C is selected from thegroup (9) defined hereinbefore is shown in Scheme XII.

[0184] Thus, a tricyclic diazepine of formula (33) wherein

[0185] and R₃ are defined hereinbefore, carrying a protecting group suchas a fluorenylalkoxycarbonyl group, preferably afluorenylmethyloxycarbonyl (P=Fmoc) group, or an alkoxycarbonylprotecting group preferably a tert-butyloxycarbonyl (P=Boc) group isreacted with a perhaloalkanoyl halide preferably trichloroacetylchloride in the presence of an organic base such as N,N-diisopropylethylamine (Hunig's base) or a tertiary amine such as triethylamine,optionally in the presence of catalytic amounts of 4-(dimethylamino)pyridine, in an aprotic organic solvent such as dichloromethane, attemperatures ranging from −10° C. to ambient to provide the desiredtrichloroacetyl intermediate of formula (34). Subsequent hydrolysis ofthe trichloroacetyl group with aqueous base such as sodium hydroxide inan organic solvent such as acetone at temperatures ranging from −10° C.to ambient, is accompanied by simultaneous removal of the protectinggroup and yields the intermediate acid of formula (35). The requiredamidation of the carboxylic acid (35) can be effectively accomplished bytreating (35) with an activating reagent such asN,N-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole,followed by reaction of the activated intermediate with an appropriatelysubstituted primary or secondary amine of formula (5) preferably in thepresence of Hunig's base or a catalytic amount of4-(dimethylamino)pyridine, in an aprotic solvent such asdichloromethane, N,N-dimethylformamide or tetrahydrofuran, attemperatures ranging from −10° C. to ambient.

[0186] Other coupling reagents known in the literature that have beenused in the formation of amide bonds in peptide synthesis can also beused for the preparation of compounds of formula (36) wherein

[0187] R and R₃ are as defined hereinbefore. The method of choice forthe preparation of compounds of formula (36) from the intermediatecarboxylic acid (35) is ultimately chosen on the basis of itscompatibility with the various substituents, and its reactivity with thetricyclic diazepine of formula (6). Subsequent reaction of a tricyclicdiazepine amide (36) with an acylating agent of formula (32) of SchemeXI provides the desired compounds of formula (I) wherein

[0188] A and R₃ are defined hereinbefore, R₄ consists of the moiety B-Cwherein B is (a) and C is the moiety (g) defined hereinbefore.

[0189] The preferred compounds of formula (I) of Scheme I wherein R₄consists of the moiety B-C wherein B is (b) and C is the moiety (g)defined hereinbefore, can be prepared in analogous fashion by replacingthe intermediate of formula (32) of Scheme XII with an appropriatelysubstituted naphthyl intermediate.

[0190] Preferred processes for the preparation of compounds of formula(I) of Scheme I wherein R₄ consists of the moiety B-C wherein B is (a)or (b) and C is (d), (e) or (f) and

[0191] A, R, R₃, R₅, R₆, R₇, R₈, R₉, and R₁₀ are defined hereinbefore,also utilize acylation of the amide intermediate (36) of Scheme XII withan acylating agent of formula (19) of Scheme IV.

[0192] An alternate preferred process for the preparation of thecompounds of formula (I) of Scheme I wherein R₄ consists of the moietyB-C wherein B is (a) and C is (g) defined hereinbefore, is shown inScheme XIII.

[0193] According to the above process a substituted tricyclic diazepineof formula (37) wherein

[0194] A, R₃, R₅, R₆ and R₇ and are defined hereinbefore, carrying aprotecting group such as a fluorenylalkoxycarbonyl group, preferably afluorenylmethyloxycarbonyl (P=Fmoc) group is reacted with aperhaloalkanoyl halide preferably trichloroacetyl chloride in thepresence of an organic base such as N,N-diisopropylethyl amine (Hunig'sbase) or a tertiary amine such as triethylamine in an aprotic organicsolvent such as dichloromethane at temperatures ranging from −10° C. toambient, to provide the desired trichloroacetyl intermediate of formula(38). Subsequent deprotection of (38) is carried out by treatment with asolution of an organic base preferably piperidine, in an organic solventsuch as N,N-dimethylformamide, at ambient temperature to provide thedesired aniline (44). Condensation of (44) with a 1,4-diketone offormula (28) either neat or in an aprotic organic solvent such asbenzene or toluene, in the presence of a catalytic amount of acarboxylic acid preferably p-toluene sulfonic acid or acetic acid , withconcomitant removal of water, at temperatures ranging from ambient to100° C. or to the reflux temperature of the solvent according to thegeneral procedure of Bruekelman et al., J. Chem. Soc. Perkin Trans. 1,2801-2807 (1984), provides the desired intermediate of formula (45).Subsequent hydrolysis of the trichloroacetyl group with aqueous basesuch as sodium hydroxide, in an organic solvent such as acetone ortetrahydrofuran, at temperatures ranging from −10° C. to the refluxtemperature of the solvent, yields the intermediate carboxylic acid offormula (46). Subsequent amidation provides the desired compounds offormula (I) wherein R₄ consists of the moiety B-C wherein B is (a) and Cis (g), and

[0195] A, R₃, R₅, R₆, R₇, R₂₉ and R₃₀ are defined hereinbefore,

[0196] The required amidation of (46) can be effectively accomplished bytreating said carboxylic acid with an activating reagent such asN,N-dicyclohexylcarbodiimide or 1-ethyl -3-(3-dimethylamino-propyl)carbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole,followed by reaction of the activated intermediate with an appropriatelysubstituted primary or secondary amine of formula (5) preferably in thepresence of Hunig's base or a catalytic amount of4-(dimethylamino)pyridine, in an aprotic solvent such asdichloromethane, N,N-dimethylformamide or tetrahydrofuran, attemperatures ranging from −10° C. to ambient. Other coupling reagentsknown in the literature that have been used in the formation of amidebonds in peptide synthesis can also be used for the preparation ofcompounds of formula (I) wherein R₄ consists of the moiety B-C wherein Bis (a) and C is (g), and

[0197] A, R₃, R₅, R₆, R₇, R₂₉ and R₃₀ are defined hereinbefore. Themethod of choice for the preparation of compounds of formula (I) fromthe intermediate carboxylic acid (46) is ultimately chosen on the basisof its compatibility with the

[0198] and R₃ groups, and its reactivity with the tricyclic diazepine offormula (6).

[0199] The desired compounds of formula (I) of Scheme XII wherein R₄consists of the moiety B-C wherein B is (b) and C is (g) can be preparedin analogous fashion by replacing the intermediate of formula (27) withan appropriately substituted naphthyl intermediate.

[0200] Alternatively, the intermediate acids of formula (35) of SchemeXII wherein

[0201] and R₃ are defined hereinbefore, can be obtained by reacting atricyclic diazepine of formula (6) with an excess of acylating agentpreferably trifluoroacetic anhydride or trichloroacetyl chloride in thepresence of an inorganic base such as potassium carbonate or an organicbase such as N,N-diisopropylethyl amine, in an aprotic solvent such asN,N-dimethylformamide, followed by basic hydrolysis of the intermediatebis-trifluoroacetyl (trichloroacetyl) intermediate of formula (39 X=F orCl), preferably with aqueous sodium hydroxide in a protic organicsolvent such as ethanol, at temperatures ranging from ambient to thereflux temperature of the solvent as exemplified in Scheme XIV.

[0202] Preferred processes for the preparation of compounds of formula(I) of Scheme I wherein R₄ consists of the moiety B-C wherein B is (a)or (b) and C is (d), (e) or (f) and

[0203] A, R, R₃, R₅, R₆, R₇, R₈, R₉, and R₁₀ are defined hereinbefore,also utilize acylation of the amide intermediate (36) of Scheme XII withan acylating agent of formula (17) of Scheme IV, as shown in Scheme XV.

[0204] Alternatively, the preferred compounds of formula (I) of Scheme Iwherein R₄ consists of the moiety B-C wherein B is (a) and C is (c) and

[0205] A, R, R₃, R₅, R₆, R₇, R₈, R₉, and R₁₀ are defined hereinbefore,can be prepared by acylation of the amide intermediate (36) of SchemeXII with an acylating agent of formula (21) of Scheme VIII, as shown inScheme XVI.

[0206] Alternatively, the preferred compounds of formula (I) of Scheme(I) wherein R₄ consists of the moiety B-C wherein B is (a) and C is (c)and

[0207] A, R, R₃, R₅, R₆, R₇, R₈, R₉, and R₁₀ are defined hereinbefore,can be prepared by acylation of the amide intermediate (36) of SchemeXII with an acylating agent of formula (19) of Scheme IV, wherein J ishereinbefore defined, as shown in Scheme XVII.

[0208] The subject compounds of the present invention were tested forbiological activity according to the following procedures.

[0209] Vasopressin Binding in Chinese Hamster Ovary cell MembranesExpressing Human Vasopressin V_(1a) Subtype Receptors

[0210] Receptor source:

[0211] Chinese hamster ovary cells (CHO cells) stably transfected withthe human vasopressin V_(1a) subtype receptors were either obtained fromBioSignal Inc., 1744 rue Williams, Montreal, Quebec, Canada or obtainedfrom M. Thibonnier, Case Western Reserve University School of Medicine,Cleveland, Ohio.

[0212] A. Passaging and Amplification of Cells:

[0213] CHO cells transfected with the human vasopressin V_(1a) subtypereceptors obtained from M. Thibonnier (pZeoSV vector) are allowed togrow to confluency (approx. >90%) in T-150 flasks under sterileconditions, in a cell culture medium of F-12 Nutrient Mixture (HAM) withL-glutamine (Gibco Cat. # 11765-054) containing 15 mM HEPES (Gibco Cat.# 15630-080), 1% antibiotic/antimycotic (add 5 mL 100x, Gibco Cat. #15240-062 per 500 mL F-1 2), 250 μg/mL Zeocin (add 1.25 mL of 100 mg/mLInvitrogen R-250-01 per 500 mL F-1 2) and 10% Fetal Bovine Serum(Qualified, heat inactivated, Gibco Cat. # 16140-063). The medium isremoved by aspiration and the cells are washed with 10 mL of Hank'sBalanced Salt solution (Gibco Cat. # 14175-095). The salt solution isremoved by aspiration and the cells are trypsinized with 5 mL oftrypsin-EDTA (0.05% trypsin, 0.53 mM EDTA-4Na, Gibco Cat. # 25300-070)for 1 min. The trypsin is removed by aspiration and the cells dislodgedby tapping. Cell Culture medium (e.g. 30 mL for 1:30 split) isimmediately added and mixed well to inactivate trypsin. 1 mL of detachedcells is added to new culture flasks containing fresh cell culturemedium (e.g., into 25 mL per T-150 flask), and mixed gently. The cellsare incubated at 37° C. in 5% CO₂. The medium is changed at 3 to 4 daysinterval (or as appropriate). The cells grow to confluency(approx. >75%-95%) within 7-8 days. All steps are done under sterileconditions.

[0214] B. Membrane Preparation:

[0215] The cells are washed twice gently with Hank's Balanced Saltsolution (e.g,. use 10 mL per T-150 flask). The excess is removed andthe cells are bathed for 15-30 min. in an enzyme-free Cell DissociationBuffer (e.g. use 8 mL Hank's Based, Gibco Cat. # 13150-016 per T-150flask) until the cells are loosened. The contents are transferred tocentrifuge tubes (50 mL) kept in an ice bath. All subsequent steps aredone at 4° C. The tubes are centrifuged at 300×g for 15 min (1380 rpm onSORVAL, Model RT6000D, using the rotor for 50 mL tubes). The supernatantis discarded and the cells suspended in homogenizing buffer(10 mMTris-HCl containing 0.25 M sucrose and 1 mM EDTA, pH 7.4) ensuring thatthe volume of the buffer is about ten times the volume of the cellpellet. The cells are pooled into a centrifuge tube (50 mL) andhomogenized with a Polytron at setting 6 for 10 sec. The homogenate istransferred into a Potter-Elvjehm homogenizer and homogenized with 3strokes. The homogenate is centrifuged at 1500×g for 10 min at 4° C.(3100 rpm using SORVAL, model RT6000D, using the rotor for 50 mL tubes).The pellet is discarded. The supernatant is centrifuged at 100,000×g for60 min. at 4° C. (Beckman L8-80M ultracentrifuge; spin at 37,500 rpmwith rotor type 70 Ti for 50 mL tubes; 38,000 rpm with type 80Ti for 15mL tubes; or 35,800 rpm with rotor type 45Ti). The supernantant isdiscarded and the pellet suspended in 3 to 4 mL of Tris buffer (50 mMTRIS-HCl, pH 7.4). The protein content is estimated by the Bradford orLowry method. The volume of the membrane suspension is adjusted with themembrane buffer (50 mM Tris-HCl containing 0.1% BSA and 0.1 mM PMSF) togive 3.0 mglmL (or as appropriate) of protein. The membranes arealiquoted and stored at −70° C.

[0216] C. Radioligand Binding Assay:

[0217] In wells of a 96-well format microtiter plate, is added 90, 110or 130 μL (to make up a final volume of 200 μL) of assay buffercontaining 50 mM of Tris-HCl (pH 7.4), BSA (heat inactivated,protease-free), 0.1% of 5 mM MgCl₂, 1 mg % aprotinin, 1 mg % leupeptin,2 mg % 1,10-phenanthroline, 10 mg % trypsin inhibitor, and 0.1 mM PMSF.The inhibitors are added on the day of the experiment. The componentsare mixed at room temperature, and then kept in ice bath followingadjustment of the pH to 7.4.

[0218] To each well is added 20 μL of unlabeled Manning ligand (to givea final concentration of 0.1 to 10 nM for standard curve and 1000 nM fornon specific binding) or test compounds in 50% DMSO (e.g. for finalconcentrations of 0.1 to 1000 nM or as appropriate) or 50% DMSO asvehicle control. 20 μL of 50% DMSO is added for Manning and otherpeptide ligands and the assay buffer volume is adjusted accordingly.

[0219] To each well is added 50 μL of frozen membrane suspension thawedimmediately prior to use and diluted in the assay buffer to the requiredconcentration (equivalent to 25 to 50 μg of protein/well as needed). 20μL of 8 nM [³H]Manning ligand in the assay buffer, prepared just beforeuse, is added, and incubated at room temperature for 60 min. shaking theplate on a mechanical shaker for the first 15 min. The incubation isstopped by rapid filtration of the the plate contents followed by washwith ice-cold buffer (50 mM Tris-HCl, pH 7.4) using a cell harvester(Tomtek and Printed filtermat-B filter paper). The filter paper isthoroughly dried (7-12 min. in a microwave oven) and impregnated withMeltiLex B/H melt-on scintillation wax sheets and the radioactivitycounted in a betaplate scintillation counter.

[0220] Vasopressin Binding in Chinese Hamster Ovary cell MembranesExpressing Human Vasopressin V₂ Subtype Receptors

[0221] Receptor Source:

[0222] Chinese Hamster Ovary (CHO) cells stably transfected with thehuman V₂ subtype receptors were obtained from M. Thibonnier, CaseWestern Reserve University School of Medicine, Cleveland, Ohio.

[0223] A. Passaging and Amplification of Cells:

[0224] CHO cells transfected with the human vasopressin V₂ subtypereceptors obtained from M. Thibonnier (pZeoSV vector) are allowed togrow to confluency (approx. >90%) in T-150 flasks under sterileconditions, in a cell culture medium of F-12 Nutrient Mixture (HAM) withL-glutamine (Gibco Cat. #11765-054) containing 15 mM HEPES (Gibco Cat. #15630-080), 1% antibiotic/antimycotic (add 5 mL 100x, Gibco Cat. #15240-062 per 500 mL F-12), 250 μg/mL Zeocin (add 1.25 mL of 100 mg/mLInvitrogen R-250-01 per 500 mL F-12) and 10% Fetal Bovine Serum(Qualified, heat inactivated, Gibco Cat. # 16140-063). The medium isremoved by aspiration and the cells washed with 10 mL of Hank's BalancedSalt solution (Gibco Cat. # 14175-095). The salt solution is removed byaspiration and the cells trypsinized with 5 mL of trypsin-EDTA (0.05%trypsin, 0.53 mM EDTA-4Na, Gibco Cat. # 25300-070) for 1 min. Thetrypsin is removed by aspiration and the cells dislodged by tapping.Cell Culture medium (e.g. 30 mL for 1:30 split) is immediately added andmixed well to inactivate trypsin. 1 mL of detached cells is added to newculture flasks containing fresh Cell Culture medium (e.g. into 25 mL perT-150 flask), and mixed gently. The cells are incubated at 37° C. in 5%CO₂. The medium is changed at 3 to 4 day interval (or as appropriate).The cells grow to confluency (approx. >75%-95%) within 7-8 days. Allsteps are done under sterile conditions.

[0225] B. Membrane Preparation:

[0226] The cells are washed twice gently with Hank's Balanced Saltsolution (e.g. use 10 mL per T-150 flask). The excess solution isremoved and the cells bathed for 15-30 min. in an enzyme-free CellDissociation Buffer (e.g. use 8 mL Hank's Based, Gibco Cat. # 13150-016per T-150 flask) until cells are loosened. The contents are transferredto centrifuge tubes (50 mL) kept in ice bath. All subsequent steps aredone at 4° C. The tubes are centrifuged at 300×g for 15 min (1380 rpm onSORVAL, Model RT6000D, using the rotor for 50 mL tubes). The supernatantis discarded and the cells suspended in homogenizing buffer (10 mMTris-HCl containing 0.25 M sucrose and 1 mM EDTA, pH 7.4) ensuring thatthe volume of the buffer is about ten times the volume of the cellpellet. The cells are pooled into a centrifuge tube (50 mL) andhomogenized with a Polytron at setting 6 for 10 sec. The homogenate istransferred into a Potter-Elvjehm homogenizer and homogenized with 3strokes. The homogenate is centrifuged at 1500×g for 60 min at 4° C.(3100 rpm using SORVAL, model RT6000D, using the rotor for 50 mL tubes).The pellet is discarded. The supernatant is centrifuged at 100,000×g for60 min. at 4° C. (Beckman L8-80M ultracentrifuge; spin at 37,500 rpmwith rotor type 70Ti for 50 mL tubes; 38,000 rpm with type 80Ti for 15mL tubes; or 35,800 rpm with rotor type 45Ti). The supernantant isdiscarded and the pellet suspended in 3 to 4 mL of Tris buffer (50 mMTRIS-HCl, pH 7.4). The protein content is estimated by the Bradford orLowry method. The volume of the membrane suspension is adjusted with themembrane buffer (50 mM Tris-HCl containing 0.1% BSA and 0.1 mM PMSF) togive 3.0 mg/mL (or as appropriate) of protein. The membranes arealiquoted and stored at −70° C.

[0227] C. Radioligand Binding Assay:

[0228] In wells of a 96-well format microtiter plate, is added 90, 110or 130 μL (to make up a final volume of 200 μL) of assay buffercontaining 50 mM of Tris-HCl (pH 7.4), BSA (heat inactivated,protease-free), 5 mM of 0.1% MgCl₂, 1 mg % aprotinin, 1 mg % leupeptin,2 mg % 1,10-phenanthroline, 10 mg % trypsin inhibitor, and 0.1 mM PMSF.The inhibitors are added on the day of the experiment. The componentsare mixed at room temperature, and then kept in ice bath followingadjustment of the pH to 7.4.

[0229] To each well is added 20 pL of unlabeled arginine vasopressin(AVP) (to give a final concentration of 0.1 to 10 nM for standard curveand 1000 nM for non specific binding) or test compounds in 50% DMSO(e.g. for final concentrations of 0.1 to 1000 nM or as appropriate) or50% DMSO as vehicle control. For vasopressin and other peptide ligands20 μL of 50% DMSO is added and the assay buffer volume is adjustedaccordingly.

[0230] To each well is added 50 μL of frozen membrane suspension thawedimmediately prior to use and diluted in assay buffer to the requiredconcentration (equivalent to 25 to 50 μg of protein/well as needed). 20μL of 8 nM [³H]arginine vasopressin ligand in the assay buffer, preparedjust before use is added and incubated at room temperature for 60 min.shaking the plate on a mechanical shaker for the first 15 min. Theincubation is stopped by rapid filtration of the plate contents followedby wash with ice-cold buffer (50 mM Tris-HCl, pH 7.4) using a cellharvester (Tomtek and Printed filtermat-B filter paper). The filterpaper is thoroughly dried (7-12 min. in a microwave oven) andimpregnated with MeltiLex B/H melt-on scintillation wax sheets and theradioactivity counted in a betaplate scintillation counter.

[0231] Oxytocin Binding in Chinese Hamster Ovary Cell MembranesExpressing Human Oxytocin Receptors

[0232] Receptor Source:

[0233] Chinese Hamster Ovary (CHO) cells stably transfected with thehuman oxytocin receptor (cf. Tanizawa et al., U.S. Pat. No. 5,466,584(1995) to Rohto Pharmaceutical Co. Ltd., Osaka, Japan) were obtainedfrom M. Thibonnier, Case Western Reserve University School of Medicine,Cleveland, Ohio.

[0234] A. Passaging and Amplification of Cells:

[0235] CHO cells transfected with the human oxytocin receptors obtainedfrom M. Thibonnier (pcDNA3.1 vector) are allowed to grow to confluency(approx. >90%) in T-150 flasks under sterile conditions, in a cellculture medium of F-12 Nutrient Mixture (HAM) with L-glutamine (GibcoCat. # 11765-054) containing 15 mM HEPES (Gibco Cat. # 15630-080), 1%antibiotic/antimycotic (add 5 mL 100x, Gibco Cat. # 15240-062 per 500 mLF-12), 400 μg/mL of Geneticin (add 4 mL of 50 mg/mL per 500 mL F-12) and10% Fetal Bovine Serum (Qualified, heat inactivated, Gibco Cat. #16140-063). The medium is removed by aspiration and the cells are washedwith 10 mL of Hank's Balanced Salt solution (Gibco Cat. # 14175-095).The salt solution is removed by aspiration and the cells trypsinizedwith 5 mL of trypsin-EDTA (0.05% trypsin, 0.53 mM EDTA-4Na, Gibco Cat. #25300-070) for 1 min. The trypsin is removed by aspiration and the cellsdislodged by tapping. Cell Culture medium (e.g. 30 mL for 1:30 split) isimmediately added and mixed well to inactivate trypsin. 1 mL of detachedcells is added to new culture flasks containing fresh Cell Culturemedium (e.g. into 25 mL per T-150 flask), and mixed gently. The cellsare incubated at 37° C. in 5% CO₂. The medium is changed at 3 to 4 daysinterval (or as appropriate). The cells grow to confluency(approx. >75%-95%) within 7-8 days. All steps are done under sterileconditions.

[0236] B. Membrane Preparation:

[0237] The cells are washed twice gently with Hank's Balanced Saltsolution (e.g., use 10 mL per T-150 flask). The excess solution isremoved and the cells bathed for 15-30 min. in an enzyme-free CellDissociation Buffer (e.g., use 8 mL Hank's Based, Gibco Cat. # 13150-016per T-150 flask) until cells are loosened. The contents are transferredto centrifuge tubes (50 mL size) kept in ice bath. All subsequent stepsare done at 4° C. The tubes are centrifuged at 300×g for 15 min (1380rpm on SORVAL, Model RT6000D, using rotor for 50 mL tubes). Thesupernatant is discarded and the cells suspended in homogenizing buffer(10 mM Tris-HCl containing 0.25 M sucrose and 1 mM EDTA, pH 7.4)ensuring that the volume of the buffer is about ten times the volume ofthe cell pellet. The cells are pooled into a centrifuge tube (50 mL) andhomogenized with a Polytron at setting 6 for 10 sec. The homogenate istransferred into a Potter-Elvjehm homogenizer and homogenized with 3strokes. The homogenate is centrifuged at 1500×g for 10 min at 4° C.(3100 rpm using SORVAL, model RT6000D, using rotor for 50 mL tubes). Thepellet is discarded. The supernatant is centrifuged at 100,000×g for 60min. at 4° C. (Beckman L8-80M ultracentrifuge; spin at 37,500 rpm withrotor type 70Ti for 50 mL tubes; 38,000 rpm with type 80Ti for 15 mLtubes; or 35,800 rpm with rotor type 45Ti). The supernantant isdiscarded and the pellet suspended in 3 to 4 mL of Tris buffer (50 mMTRIS-HCl, pH 7.4). The protein content is estimated by the Bradford orLowry method. The volume of the membrane suspension is adjusted with themembrane buffer (50 mM Tris-HCl containing 0.1% BSA and 0.1 mM PMSF) togive 3.0 mg/mL (or as appropriate) of protein. The membranes arealiquoted and stored at −70° C.

[0238] C. Radioligand Binding Assay:

[0239] In wells of a 96-well format microtiter plate, is added 90, 110or 130 μL (to make up a final volume of 200 AL) of assay buffercontaining 50 mM of Tris-HCl (pH 7.4), BSA (heat inactivated,protease-free), 5 mM of 0.1% MgCl₂, 1 mg % aprotinin, 1 mg % leupeptin,2 mg % 1,10-phenanthroline, 10 mg % trypsin inhibitor, and 0.1 mM PMSF.The inhibitors are added on the day of the experiment. The componentsare mixed at room temperature, and then kept in ice bath followingadjustment of the pH to 7.4.

[0240] To each well is added 20 μL of unlabeled oxytocin (to give afinal concentration of 0.1 to 10 nM for standard curve and 1000 nM fornon specific binding) or test compounds in 50% DMSO (e.g. for finalconcentrations of 0.1 to 1000 nM or as appropriate) or 50% DMSO asvehicle control. For oxytocin and other peptide ligands, 20 μL of 50%DMSO is added and the assay buffer volume is adjusted accordingly.

[0241] To each well is added 50 μL of frozen membrane suspension thawedimmediately prior to use and diluted in assay buffer to the requiredconcentration (equivalent to 25 to 50 μg of protein/well as needed). 20μL of 8 nM [³H]oxytocin in the assay buffer, prepared just before use isadded and incubated at room temperature for 60 min. shaking the plate ona mechanical shaker for the first 15 min. The incubation is stopped byrapid filtration of the plate contents followed by washing with ice-coldbuffer (50 mM Tris-HCl, pH 7.4) using a cell harvester (Tomtek andPrinted filtermat-B filter paper). The filter paper is thoroughly dried(7-12 min. in a microwave oven) and impregnated with MeltiLex B/Hmelt-on scintillation wax sheets and the radioactivity counted in abetaplate scintillation counter.

[0242] Binding data is either reported as percent inhibition at acertain concentration or if an IC₅₀ was calculated, as a nanomolarconcentration.

[0243] The results of these tests on representative compounds of thisinvention are shown in Table I. TABLE 1 Binding to membranes of ChineseHamster Ovary (CHO) cell line stably transfected with human vasopressinV_(1a) receptor subtype, human vasopressin V₂ receptor subtype and humanoxytocin receptor OT % V_(1a) V₂ Exam- inhibition @ 100% % inhibition @100 % inhibition @ 100 ple nM (IC₅₀, nM)* nM (IC_(50,) nM)* nM (IC₅₀,nM)*  2 (12.46) (2718.5) (1759.2)  3 37 −8 22  4 (8.89) 14 24  5 24 −6 3 6 56 2 13  7 (11.4) (2481.3) (2459.18)  8 (6.37) (1370) (1475)  9 32 1042  11 (3.44) (70.41) (1351)  12 21 −10 −1  13 33 4 −4  14 9 −16 −3  15−4 −8 27  17 28 −11 32  18B (14.5) (386) (189)  19D 97 51 84  20 (1.81)(717) (4355)  21 (1.7) (378) (1163)  22 (1.74) (225) (1428)  24 (8.0)(22.5) (4.7)  25 (55.8) (130.6) (11.3)  26 17 −3 3  27 (18.1) (45.6)(148.9)  28 (29.51) (66.56) (58.82)  29 51 74 24  30 48 8 3  31 69 30 31 32 (185) (>3000) (605)  33 101 68 11  43 (1.66) (312) (409)  47 (6.61)(1004) (722)  48 (6.7) (484) (700)  49 92 5 27  50 95 40 15  51 81 14 17 52 86 54 17  53 89 38 23  54 78 −4 7  55 67 4 30  56 68 2 27  57 76 1511  58 24 5 18  59 (16.45) (1886) (2307)  60 (5.39) (681) (1203)  61(4.5) (316.4) (744.6)  62 91 10 27  63 98 57 9  64 74 13 19  65 68 40 6 66 87 52 20  67 79 −4 4  68 64 9 29  69 71 8 22  70 75 19 11  71 25 413  72 74 8 26  73 85 46 21  74 45 12 14  75 66 27 14  76 65 58 17  7765 44 28  78 62 −3 14  79 35 0 7  80 44 16 43  81 43 4 21  82 50 37 10 83 10 8 18  84 48 1 11  85 (3.02) (788) (3126)  86 (2.31) (172) (1698) 87 (4.63) (349) (2176)  88 98 44 30  89 97 50 13  90 100 63 19  91 9790 17  92 99 78 20  93 90 29 36  94 94 28 26  95 97 68 13  96 54 10 24 97 (7.14) (1092) (2004)  98 (2.48) (238) (1026)  99 (2.04) (311) (1333)100 98 27 26 101 100 75 7 102 95 45 18 103 98 43 11 104 96 85 20 105 9774 18 106 88 22 34 107 87 15 19 108 96 52 8 109 49 9 14 110 (7.93) (661)(788) 111 (6.7) (458.7) (772.3) 112 89 8 32 113 97 45 9 114 76 11 22 11525 11 12 116 84 42 22 117 70 −3 14 118 54 14 39 119 58 9 15 120 69 20 6121 0 0 13 122 77 8 8 123 47 9 15 124 60 16 21 125 36 10 8 126 43 9 18127 29 16 3 128 43 18 17 129 52 6 5 130 46 4 5 131 26 8 13 132 31 2 16133 46 20 8 134 15 5 16 135 24 2 1 136 (7.19) (538) (597) 137 88 4 −4138 95 47 29 139 76 9 12 140 87 24 29 141 −6 −3 8 142 83 46 −5 143 69 −37 144 53 −1 3 145 53 −4 −5 146 78 37 12 147 33 3 20 148 78 −9 1 149 7517 20 150 75 42 18 151 47 17 6 152 63 23 10 153 60 50 11 154 54 39 9 15556 0 15 156 30 2 12 157 38 5 23 158 50 16 19 159 50 44 16 160 20 6 24161 53 8 4 162 71 18 20 163 82 43 13 164 54 23 16 165 64 24 25 166 27 293 167 60 50 20 168 52 8 10 169 36 9 5 170 47 21 27 171 40 14 14 172 4743 11 173 21 0 17 174 59 8 7 175 98 28 17 176 88 27 18 177 98 42 18 17893 79 15 179 93 73 23 180 98 26 14 181 100 23 12 182 70 14 35 183 97 2618 184 83 0 9 185 95 37 27 186 97 53 8 187 100 81 31 188 96 89 10 189 9983 22 190 99 40 9 191 100 41 17 192 91 31 28 193 96 41 16 194 96 23 0195 (3.84) (367) (298) 196 (11.63) (1243) (855) 197 (5.39) (524) (497)198 94 50 19 199 84 23 6 200 87 64 10 201 86 43 19 202 73 2 8 203 62 428 204 72 16 6 205 24 −6 18 206 (3.66) (317) (190) 207 (9.5) (488)(601.1) 208 81 20 12 209 81 64 10 210 82 39 17 211 87 45 23 212 95 35 43213 70 12 33 214 64 8 11 215 26 5 22 216 82 10 0 217 98 21 34 218 98 4523 219 (12.07) (1807) (1324) 220 (7.2) (387) (1816) 221 (11.1) (818)(832.7) 222 84 15 1 223 71 12 13 224 −3 1 7 225 87 35 −4 226 71 3 10 22769 2 2 228 77 22 20 229 19 8 27 230 67 3 4 231 63 7 −5 232 81 13 4 23386 31 23 234 82 26 22 235 64 9 17 236 46 6 5 237 79 39 −3 238 79 3 27239 61 2 16 240 62 1 9 241 51 −4 −17 242 69 33 25 243 17 5 21 244 68 449 245 (16.91) (933) (423) 246 (17.8) (373) (508.2) 247 97 62 21 248 7717 7 249 18 12 9 250 87 53 −10 251 87 6 24 252 72 8 21 253 71 16 −10 25466 7 −4 255 80 53 27 256 33 7 40 257 85 10 16 258 (2.85) (913) (5679)259 97 21 −3 260 102 55 20 261 52 13 18 262 76 8 4 263 (2.31) (202)(4124) 264 94 67 12 265 100 31 10 266 97 49 −17 267 93 12 24 268 90 6 34269 88 −1 −19 270 95 40 25 271 (6.29) (983) (1915) 272 (2.61) (301)(1302) 273 (4.26) (481.07) (811.98) 274 103 90 32 275 89 9 21 276 74 4−3 277 41 8 19 278 (7.87) (303) (1679) 279 100 39 17 280 95 77 6 281 9358 −9 282 84 1 −17 283 91 40 29 284 87 0 12 285 93 38 32 286 86 8 27 28788 0 26 288 95 24 32 289 45 6 7 290 78 47 −6 291 32 2 5 292 69 6 −7 29353 2 3 294 54 −3 −2 295 79 6 22 296 88 31 24 297 73 −2 13 298 94 20 29299 86 14 22 300 72 −2 19 301 82 1 9 302 64 −15 17 303 66 −4 14 304 74−7 19 306 34 0 0 307 30 −7 8 308 7 −12 1 309 72 11 7 310 58 4 12 311 16−5 7 312 16 7 3 313 32 2 2 314 19 6 7 315 10 7 −4 316 24 0 −2 317 32 1015 318 32 5 17 319 22 9 13 320 34 4 21 321 62 5 23 322 66 12 24 323F 332 5

[0244] The following Examples are presented to illustrate rather thanlimit the scope of this invention.

EXAMPLE 110-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid

[0245] Step A. 4-Bromo-3-methylbenzoic acid methyl ester

[0246] To a suspension of 4-bromo-3-methylbenzoic acid (10.0 g, 46.5mmol) in methanol (125 mL) was added concentrated sulfuric acid (1 mL).The reaction was heated at reflux overnight with a homogeneous solutionobtained after several minutes of heating. After cooling, the methanolwas removed in vacuo and the residue was dissolved in dichloromethaneand washed with saturated aqueous sodium bicarbonate. The organic phasewas dried over anhydrous sodium sulfate, filtered and concentrated invacuo to give 10.2 g of title compound as a brown solid, m.p. 41-43° C.

[0247]¹H NMR (DMSO-d₆, 400 MHz): δ2.39 (s, 3H), 3.85 (s, 3H), 7.64-7.72(m, 2H), 7.88-7.89 (m, 1H). MS [EI, m/z]: 228[M]⁺.

[0248] Anal. Calcd. for C₉H₉BrO₂: C, 47.19, H, 3.90. Found: C, 47.22, H,3.80.

[0249] Step B.(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carboxylic acid methylester

[0250] A mixture of 4-bromo-3-methylbenzoic acid methyl ester of Step A(2.0 g, 8.7 mmol), 2-trifluoromethyl-phenyl boronic acid (1.65 g, 8.7mmol) and sodium carbonate (4.1 g, 38.7 mmol) in toluene:ethanol:water(50 mL: 25 mL: 25 mL) was purged with nitrogen for 1 hour. Afteraddition of the tetrakis(triphenylphosphine) palladium(0) catalyst (0.50g, 0.43 mmol) the reaction was heated at 100° C. overnight. The cooledreaction mixture was filtered through Celite and the cake washed withethyl acetate. The organic layer was washed with water, dried overanhydrous. sodium sulfate, filtered and concentrated in vacuo to give abrown oil. Purification by flash chromatography with a solvent gradientof 25% to 50% dichloromethane in hexane provided 2.0 g of the titlecompound as a colorless oil.

[0251]¹H NMR (DMSO-d₆, 400 MHz): δ2.03 (s, 3H), 3.88 (s, 3H), 7.26 (d,1H), 7.34 (d, 1H), 7.66 (t, 1H), 7.75 (t, 1H), 7.81-7.83 (m, 1H),7.86-7.88 (m, 1H), 7.90-7.91 (m, 1H). MS [(+)ESI, m/z]: 312[M+NH₄]⁺.

[0252] Anal. Calcd. for C₁₆H₁₃F₃O₂: C, 65.31, H, 4.45. Found: C, 64.92,H, 4.54.

[0253] Step C.(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carboxylic acid

[0254] To a solution of(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carboxylic acid methylester of Step B (1.9 g, 6.5 mmol) in tetrahydrofuran (30 mL) was added 1N sodium hydroxide (13 mL, 13 mmol). The reaction mixture was heated atreflux overnight, then cooled and acidified with 2 N hydrochloric acid.The aqueous layer was extracted with ethyl acetate and the combinedextracts were dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give 1.65 g of the title compound as a whitesolid, m.p. 171-174° C.

[0255]¹H NMR (DMSO-d₆, 400 MHz): δ2.02 (s, 3H), 7.23 (d, 1H), 7.34 (d,1H), 7.65 (t, 1H), 7.75 (t, 1H), 7.79-7.81 (m, 1H), 7.86-7.89 (m, 2H),13.00 (brs, 1H). MS [(−)ESI, m/z]: 279[M−H]⁻.

[0256] Anal. Calcd. for C₁₅H₁₁F₃O₂: C, 64.29, H, 3.96. Found: C, 64.26,H, 3.80.

[0257] Step D. (10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanone

[0258] A suspension of(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carboxylic acid ofStep C (0.50 g, 1.78 mmol) in thionyl chloride (3 mL) was heated atreflux for 90 minutes. After cooling, the thionyl chloride was removedin vacuo and the residue dissolved in toluene. The solution wasconcentrated in vacuo to yield the crude acid chloride as a brown oil.The acid chloride was dissolved in dichloromethane (5 mL) and slowlyadded to a solution of 10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine (0.49 g, 2.66 mmol) and N,N-diisopropylethyl amine (0.68mL, 3.90 mmol) in dichloromethane (15 mL). After stirring for 2 hours,the reaction was quenched with water. The organic layer was sequentiallywashed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, driedover anhydrous sodium sulfate, filtered and concentrated in vacuo togive a yellow foam. Purification by flash chromatography on silica gelusing a solvent gradient of 15 to 25% ethyl acetate in hexane gave awhite foam which was crystallized upon sonication in ethanol/hexane toprovide the title compound (0.55 g) as a white solid, m.p. 127-130° C.

[0259]¹H NMR (DMSO-d₆, 400 MHz): δ1.86 (s, 3H), 4.80-5.40 (br, 4H),5.93-5.98 (m, 2H), 6.85 (t, 1H), 6.91-6.96 (m, 2H), 7.03-7.05 (m, 1H),7.10-7.14 (m, 1H), 7.19-7.24 (m, 2H), 7.29 (s, 1H), 7.47-7.49 (m, 1H),7.61 (t, 1H), 7.70 (t, 1H), 7.81 (d, 1H). MS [EI, m/z]: 446[M]⁺.

[0260] Anal. Calcd. for C₂₇H₂₁F₃N₂O: C, 72.64, H, 4.74, N, 6.27. Found:C, 72.48, H, 4.57, N, 6.16.

[0261] Step E.2,2,2-Trichloro-1-(10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10.11-dihydro-5H-pyrrolo[2,1-c][1,4] benzodiazepin-3-yl)ethanone

[0262] To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanoneof Step D (1.87 g, 4.19 mmol) in dichloromethane (20 mL) was addedN,N-diisopropylethyl amine (1.46 mL, 8.38 mmol) followed by the slowaddition of trichloroacetyl chloride (1.45 mL, 13.0 mmol). The reactionmixture was stirred overnight at room temperature, and then quenchedwith water. The organic phase was washed with 0.1 N hydrochloric acidfollowed by water, then dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to give a green oil. Purification by flashchromatography on silica gel using a solvent system of 20% ethyl acetatein hexane provided 2.2 g of title product as a pale, yellow foam.

[0263]¹H NMR (DMSO-d6, 400 MHz): δ1.84 (s, 3H), 5.25 (br, 2H), 5.97 (br,2H), 6.37 (d, 1H), 6.89-6.92 (m, 2H), 7.02-7.04 (m, 1H), 7.06-7.10 (m,1H), 7.15-7.22 (m, 2H), 7.28 (s, 1H), 7.41-7.46 (m, 2H), 7.58 (t, 1H),7.67 (t, 1H), 7.79 (d, 1H). MS [(+)APCI, m/z]: 591[M+H]⁺.

[0264] Anal. Calcd. for C₂₉H₂₀C₁₃F₃N₂O₂+0.20 C₄H₈O₂+0.80H₂O: C, 57.37,H, 3.75, N, 4.49. Found: C, 57.06, H, 3.39, N, 4.50.

[0265] Step F.10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo [2,1-c][1,4] benzodiazepine-3-carboxylic acid

[0266] To a solution of2,2,2-trichloro-1-(10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4] benzodiazepin-3-yl)ethanone of Step E (2.3 g, 3.9 mmol) inacetone (20 mL) was added 2.5 N sodium hydroxide (3.1 mL, 7.8 mmol).After stirring overnight, the reaction mixture was acidified with 2 Nhydrochloric acid (4.3 mL, 8.6 mmol) and then concentrated in vacuo. Theresidue was partitioned between ethyl acetate and water. The organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedin vacuo to give a brown solid. Trituration with diethyl ether/hexaneprovided the title compound (1.32 g) as a white solid, m.p. 233-235° C.¹H NMR (DMSO-d₆, 400 MHz): δ1.84 (s, 3H), 5.17 (br, 2H), 5.94 (br, 2H),6.10-6.11 (m, 1H), 6.76 (d, 1H), 6.85-6.91 (m, 2H), 7.00-7.06 (m, 2H),7.12-7.16 (m, 1H), 7.21 (d, 1H), 7.25 (s, 1H), 7.32-7.34 (m, 1H), 7.59(t, 1H), 7.68 (t, 1H), 7.79 (d, 1H), 12.33 (br, 1H). MS [(+)ESI, m/z]:491[M+H]⁺.

[0267] Anal. Calcd. for C₂₈H₂₁F₃N₂O₃: C, 68.57, H, 4.32, N, 5.71. Found:C, 68.39, H, 4.25, N 5.64.

EXAMPLE 2(4-Methyl-piperazin-1-yl)-[10-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl-methanone

[0268] A suspension of10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (1.65g, 3.36 mmol) in dichloromethane (15 mL) containing a few drops of N,N-dimethylformamide was treated dropwise under nitrogen with oxalylchloride (0.38 mL, 4.36 mmol). After the gas evolution subsided, thereaction mixture was refluxed for an additional 15 min. The cooledsolution was evaporated to dryness to give the crude acid chloride as abrown solid. The acid chloride was then dissolved in dichloromethane (10mL) and slowly added to a solution of 1-methylpiperazine (1.5 mL, 13.5mmol) and N,N -diisopropylethyl amine (3.5 mL, 20.1 mmol) indichloromethane (25 mL). After stirring overnight, the reaction wasquenched with water. The organic layer was sequentially washed with 1 Nhydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give a brown oil.Purification by flash chromatography on silica gel using a solventsystem of 10% methanol in ethyl acetate gave a pale yellow foam whichwas crystallized from diethyl ether to provide the desired titlecompound (1.17 g) as a white solid.

[0269]¹H NMR (DMSO-d₆, 400 MHz): δ1.83 (s, 3H), 2.20 (s, 3H), 2.31-2.33(m, 4H), 3.61-3.63 (m, 4H), 5.15 (br, 2H), 5.40 (s, 2H), 6.06 (d, 1H),6.23 (d, 1H), 6.85-6.90 (m, 2H), 6.99-7.06 (m, 2H), 7.12-7.16 (m, 1H),7.20 (d, 1H), 7.25 (s, 1H), 7.37-7.39 (m, 1H), 7.58 (t, 1H), 7.67 (t,1H), 7.79 (d, 1H). MS [(+)ESI, m/z]: 573[M+H]⁺.

[0270] Anal. Calcd. for C₃₃H₃₁F₃N₄O₂: C, 69.22, H, 5.46, N, 9.78. Found:C, 68.79, H, 5.45, N 9.72.

EXAMPLE 310-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acidbis-(3-dimethylamino-propyl)-amide

[0271] A suspension of 10-[(2-methyl-2′-trifluoromethyl-[1,1l′-biphenyl]-4-yl)r-arbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (0.50g, 1.02 mmol) in dichloromethane (5 mL) containing a few drops of N,N-dimethylformamide was treated dropwise under nitrogen with oxalylchloride (0. 12 mL, 1.38 mmol). After gas evolution subsided, thereaction mixture was refluxed for an additional 15 minutes. The cooledsolution was evaporated to dryness to give the crude acid chloride as abrown solid. The acid chloride was then dissolved in dichloromethane (5mL) and slowly added to a solution of bis-(3-dimethylamino-propyl)-amine(0.90 mL, 4.04 mmol) and N,N-diisopropylethyl amine (1.1 mL, 6.31 mmol)in dichloromethane (5 mL). After stirring for 2 hours, the reaction wasquenched with water. The organic layer was sequentially washed with 1 Nhydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give a brown oil.Purification was achieved by preparative HPLC on a Primesphere S C18column (0.21×15 cm) using a solvent gradient from 60:40:0.1 to 80:20:0.1acetonitrile-water -trifluoroacetic acid. After removal of theacetonitrile in vacuo, the aqueous solution was basified with 2.5 Nsodium hydroxide then extracted with dichloromethane. The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give the title compound (0.24 g) as a whitefoam, m.p. 55-64 ° C.

[0272]¹H NMR (DMSO-d₆, 400 MHz): δ1.68 (br, 4H), 1.83 (s, 3H), 2.00-2.23(br, 16H), 3.43 (t, 4H), 5.10 (br, 2H), 5.34 (s, 2H), 6.04 (d, 1H), 6.21(d, 1H), 6.87-6.90 (m, 2H), 6.99-7.04 (m, 2H), 7.13 (t, 1H), 7.21 (d,1H), 7.24 (s, 1H), 7.31-7.33 (m, 1H), 7.58 (t, 1H), 7.67 (t, 1H), 7.79(d, 1H). MS [(+)ESI, m/z]: 660[M+H]⁺.

[0273] Anal. Calcd. for C₃₈H₄₄F₃N₅O₂: C, 69.18, H, 6.72, N, 10.61.Found: C, 68.26, H, 6.68, N 10.43.

EXAMPLE 4 [4-(3-Dimethylaminopropyl)-piperazin-1-yl]-[10-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-methanone

[0274]10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, StepF (0.50 g, 1.02 mmol), 1-[3-(dimethylamino)propyl]piperazine (0.21 mL,1.23 mmol) and 1-hydroxybenzotriazole monohydrate (0.15 g, 1.11 mmol)were dissolved in N,N -dimethylformamide (4 mL).1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.22 g,1.15 mmol) was then added followed by N,N-diisopropylethyl amine (0.27mL, 1.55 mmol). The reaction mixture was stirred overnight, diluted withethyl acetate and washed with water and saturated aqueous sodiumbicarbonate. The organic phase was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give a yellow oil. Purification byflash chromatography on silica gel using a solvent system of 10%methanol in chloroform provided the title compound (0.19 g) as a whitefoam, m.p. 85-95° C.

[0275]¹H NMR (DMSO-d₆, 400 MHz): δ1.52-1.60 (m, 2H), 1.83 (s, 3H), 2.13(s, 6H), 2.25 (t, 2H), 2.31 (t, 2H), 2.37 (br, 4H), 3.61 (br, 4H), 5.15(br, 2H), 5.40 (s, 2H), 6.05 (d, 1H), 6.22 (d, 1H), 6.84-6.90 (m, 2H),6.98-7.06 (m, 2H), 7.14 (t, 1H), 7.21 (d, 1H), 7.25 (s, 1H), 7.37-7.39(m, 1H), 7.58 (t, 1H), 7.68 (t, 1H), 7.79 (d, 1H). MS [(+)ESI, m/z]:644[M+H]⁺.

[0276] Anal. Calcd. for C₃₇H₄₀F₃N₅O₂+0.40H₂O: C, 68.26, H, 6.32, N,10.76. Found: C, 67.94, H, 6.37, N, 10.46.

EXAMPLE 5[3-Methyl-4-(3-methyl-phenyl)-piperazin-1-yl]-[10-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-0,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl-methanone

[0277]10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, StepF (0.50 g, 1.02 mmol), 2-methyl-1-(3-methylphenyl)piperazine (0.24 mL,1.26 mmol) and 1-hydroxybenzotriazole monohydrate (0.15 g, 1.11 mmol)were dissolved in N,N -dimethylformamide (5 mL).1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.22 g,1.15 mmol) was then added followed by N,N-diisopropylethyl amine (0.27mL, 1.55 mmol). The reaction mixture was stirred overnight, diluted withethyl acetate and washed with water and saturated aqueous bicarbonate.The organic phase was then dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to give a brown oil. Purification by flashchromatography on silica gel using a solvent system of 40% ethyl acetatein hexane provided a white foam which was redissolved in dichloromethaneand evaporated to dryness in vacuo prior to use in the next step.

[0278]¹H NMR (DMSO-d₆, 400 MHz): δ0.91 (d, 3H), 1.83 (s, 3H), 2.24 (s,3H), 3.00-3.05 (m, 1H), 3.28-3.32 (m, 2H), 3.46-3.49 (m, 1H), 3.99-4.07(m, 2H), 4.22-4.25 (m, 1H), 5.15 (br, 2H), 5.40-5.49 (m, 2H), 6.09 (d,1H), 6.31 (d, 1H), 6.59 (d, 1H), 6.70-6.73 (m, 2H), 6.85-6.90 (m, 2H),6.99-7.15 (m, 4H), 7.20 (d, 1H), 7.26 (s, 1H), 7.36 (d, 1H), 7.58 (t,1H), 7.67 (t, 1H), 7.79 (d, 1H). MS [(+)ESI, m/z]: 663[M+H]⁺.

[0279] Anal. Calcd. for C₄₀H₃₇F₃N₄O₂+O0.13 CH₂C₁₂+0.17 C₄H₈O₂: C, 71.17,H, 5.65, N, 8.13. Found: C, 70.85, H, 5.50, N, 8.01.

EXAMPLE 64-[[10,11-Dihydro-10-[[2-methyl-2′-trifluoromethyl[1,1′-biphenyl]-4-yl]carbonyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]carbonyl]-1-piperazine-carboxylicacid, tert-butyl ester

[0280]10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, StepF (1.0 g, 2.04 mmol), 1-(tert-butoxycarbonyl)piperazine (0.46 g, 2.47mmol) and 1-hydroxybenzotriazole monohydrate (0.30 g, 2.22 mmol) weredissolved in N,N -dimethylformamide (8 mL).1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.43 g,2.24 mmol) was then added followed by N,N-diisopropylethyl amine (0.55mL, 3.09 mmol). The reaction mixture was stirred overnight, diluted withethyl acetate and washed with water and saturated aqueous sodiumbicarbonate. The organic phase was then dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give a brown oil.Purification by flash chromatography using a solvent gradient from 30%to 50% ethyl acetate in hexane provided the desired title compound as awhite foam, which was redissolved in dichloromethane and evaporated todryness in vacuo prior to use in the next step.

[0281]¹H NMR (DMSO-dr, 400 MHz): δ1.41 (s, 9H), 1.83 (s, 3H), 3.38 (br,4H), 3.59-3.61 (m, 4H), 5.15 (br, 2H), 5.41 (s, 2H), 6.07 (d, 1H), 6.28(d, 1H), 6.85-6.90 (m, 2H), 6.99-7.06 (m, 2H), 7.12-7.16 (m, 1H), 7.21(d, 1H), 7.25 (s, 1H), 7.40-7.42 (m, 1H), 7.58 (t, 1H), 7.67 (t, 1H),7.79 (d, 1H). MS [(+)APCI, m/z]: 659[M+H]⁺.

[0282] Anal. Calcd. for C₃₇H₃₇F₃N₄O₄+0.09 CH₂C₁₂+0.18 C₄H₈O₂: C, 66.56,H, 5.71, N, 8.21. Found; C, 66.27, H, 5.40, N, 8.00.

EXAMPLE 710,11-Dihydro-10-[[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepinehydrochloride salt

[0283] The4-[[10,11-dihydro-10-[[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]carbonyl]-1-piperazine-carboxylicacid, tert-butyl ester of Example 6 (0.85 g, 1.29 mmol) was added in oneportion to stirred ethyl acetate (10 mL) saturated with hydrogenchloride gas at 0° C. A precipitate formed after several minutes. Thereaction mixture was stirred for 90 minutes under anhydrous conditions.The reaction was then warmed to room temperature and diluted withdiethyl ether. The precipitated product was collected by filtration anddried under high vacuum to provide the desired title compoundhydrochloride salt (0.65 g) as an off-white foam.

[0284]¹H NMR (DMSO-d₆, 400 MHz): δ1.84 (s, 3H), 3.16 (br, 4H), 3.83-3.85(m, 4H), 5.15 (br, 2H), 5.43 (s, 2H), 6.09 (d, 1H), 6.38 (d, 1H),6.87-6.91 (m, 2H), 6.99-7.01 (m, 1H), 7.06 (t, 1H), 7.13-7.17 (m, 1H),7.21 (d, 1H), 7.26 (s, 1H), 7.44-7.46 (m, 1H), 7.59 (t, 1H), 7.68 (t,1H), 7.79 (d, 1H), 9.28 (br, 2H). MS [(+)APCI, m/z]: 559[M+H]⁺.

[0285] Anal. Calcd. for C₃₂H₂₉F₃N₄O₂+1.0 HCl +1.00 H₂O+0.06 C₄H₁₀O: C,62.70, H, 5.32, N 9.07. Found: C, 62.42, H, 5.22, N, 8.94.

EXAMPLE 8N-[(10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]guanidine

[0286]10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]4-yl)-carbonyl]-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, StepF (0.50 g, 1.02 mmol) and 1,1′-carbonyldiimidazole (0.17 g, 1.05 mmol)were dissolved in anhydrous N,N-dimethylformamide (5 mL). After stirringfor 30 minutes, guanidine carbonate (0.19 g, 1.05 mmol) was added, andthe reaction was heated to 100° C. for 4 hours. After cooling, thereaction mixture was diluted with water and extracted with ethylacetate. The organic layers were combined and dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give an orangeoil. Purification was achieved by preparative HPLC on a Primesphere 5C18 (0.2×15 cm) column using a solvent gradient from 55:45:0.1 to90:10:0.1 acetonitrile-water-trifluoroacetic acid. After removal of theacetonitrile in vacuo, the aqueous solution was neutralized withsaturated aqueous sodium bicarbonate, and then extracted with ethylacetate. The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give 0.25 g of the titlecompound as a white solid.

[0287]¹H NMR (DMSO-d₆, 400 MHz): δ1.85 (s, 3H), 5.15 (br, 2H), 6.00 (d,1H), 6.20 (br, 2H), 6.65 (d, 1H), 6.80 (d, 1H), 6.97 (d, 1H), 6.96-7.01(m, 2H), 7.11 (t, 1H), 7.22-7.25 (m, 2H), 7.36-7.38 (m, 1H), 7.60 (t,1H), 7.69 (t, 1H), 7.80 (d, 1H). MS [(+)APCI, m/z]: 532[M+H]⁺.

[0288] Anal. Calcd. for C₂₉H₂₄F₃N₅O₂+0.15 C₄H₈O₂: C, 65.26, H, 4.66, N,12.86. Found: C 64.53, H, 4.45, N, 12.77.

EXAMPLE 910-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid

[0289] Step A. (2-Methyl-2′-methoxy-[1,1′-biphenyl]-4-yl)carboxylic acidmethyl ester

[0290] A mixture of 3-methyl-4-bromobenzoic acid methyl ester (2.0 g,8.7 mmol), 2-methoxyphenyl boronic acid (1.32 g, 8.7 mmol) and sodiumcarbonate (4.1 g, 38.7 mmol) in toluene:ethanol:water (50 mL:25 mL: 25mL) was purged with nitrogen for 1 hour. After addition of thetetrakis(triphenylphosphine) palladium(0) catalyst (0.50 g, 0.43 mmol),the reaction mixture was heated at 100° C. overnight. After cooling, thereaction was filtered through Celite and the cake washed with ethylacetate. The organic layer was washed with water, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give a brown oil.Purification by flash chromatography on silica gel with a solventgradient from 20% to 50% dichloromethane in hexane gave 2.0 g of productas a colorless oil.

[0291]¹H NMR (DMSO-d₆, 400 MHz): δ2.09 (s, 3H), 3.70 (s, 3H), 3.85 (s,3H), 7.00-7.04 (m, 1H), 7.08-7.11 (m, 2H), 7.23 (d, 1H), 7.37-7.41 (m,1H), 7.77-7.79 (m, 1H), 7.83-7.84 (m, 1H). MS [(+)APCI, m/z]: 257[M+H]⁺.

[0292] Anal. Calcd. for C₁₆H₁₆O₃: C, 74.98, H, 6.29. Found: C, 74.06, H,6.17.

[0293] Step B. (2-Methyl-2′-methoxy-[1,1′-biphenyl]-4-yl)carboxylic acid

[0294] The (2-methyl-2′-methoxy-[1,1′-biphenyl]-4yl)carboxylic acidmethyl ester of Step A (1.9 g, 7.4 mmol) was dissolved intetrahydrofuran (30 mL) and 1 N sodium hydroxide (15 mL, 15 mmol) wasadded. The reaction mixture was heated at reflux overnight, then cooledand acidified with 2 N hydrochloric acid. The aqueous layer wasextracted with ethyl acetate. The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated in vacuo togive 1.6 g of product as a white solid, m.p. 160-162 ° C.

[0295]¹H NMR (DMSO-d₆, 400 MHz): δ2.09 (s, 3H), 3.70 (s, 3H), 7.00-7.03(m, 1H), 7.08-7.10 (m, 2H), 7.20 (d, 1H), 7.36-7.40 (m, 1H), 7.75-7.78(m, 1H), 7.82 (s, 1H), 12.85 (br, 1H). MS [(−) APCI, m/z]: 241[M−H]⁻.

[0296] Anal. Calcd. for C₁₅H₁₄O₃: C, 74.36, H, 5.82. Found: C, 73.93, H,5.71.

[0297] Step C.(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)-methanone

[0298] The (2-methyl-2′-methoxy-[1,1′-biphenyl]4-yl)carboxylic acid ofStep B (0.50 g, 2.06 mmol) was suspended in thionyl chloride (3 mL) andthe mixture heated at reflux for 30 minutes. After cooling, the thionylchloride was removed in vacuo. The residue was dissolved in toluene andconcentrated in vacuo to give the crude acid chloride as a brown oil.The acid chloride was then dissolved in dichloromethane (5 mL) andslowly added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.57 g, 3.10 mmol) and N,N-diisopropylethylamine (0.79 mL, 4.53 mmol) in dichloromethane (15 mL). After stirringfor 1 hour, the reaction was quenched with water. The organic layer waswashed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, driedover anhydrous sodium sulfate, filtered and concentrated in vacuo togive a yellow foam. Purification by flash chromatography using a solventgradient of 5 to 15% ethyl acetate in hexane yielded a white foam whichcrystallized upon sonication in ethanol/hexane to give 0.42 g of thedesired title product as a white solid, m.p. 133-135° C.

[0299]¹H NMR (DMSO-d₆, 400 MHz): δ1.93 (s, 3H), 3.65 (s, 3H), 4.80-5:40(br, 4H), 5.92-5.96 (m, 2H), 6.81-6.82 (m, 1H), 6.89-6.91 (m, 1H),6.95-7.05 (m, 5H), 7.16-7.25 (m, 3H), 7.31-7.35 (m, 1H), 7.47-7.49 (m,1H). MS [(+)ESI, m/z]: 409[M+H]⁺.

[0300] Anal. Calcd. for C₂₇H₂₄N₂O₂: C, 79.39, H, 5.92, N, 6.86. Found:C, 79.16, H, 5.87, N, 6.90.

[0301] Step D.2,2,2-Trichloro-1-{10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl} ethanone

[0302] To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)-methanoneof Step C (1.5 g, 3.67 mmol) in dichloromethane (20 mL) was addedN,N-diisopropylethyl amine (1.28 mL, 7.35 mmol) followed by slowaddition of trichloroacetyl chloride (1.23 mL, 11.0 mmol). The reactionmixture was stirred overnight at room temperature then quenched withwater. The organic phase was washed with 0.1 N hydrochloric acidfollowed by water, then dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to give a green oil. Purification by flashchromatography on silica gel using a solvent system of 20% ethyl acetatein hexane provided 2.1 g of title compound. The material was redissolvedin dichloromethane and evaporated to dryness to provide a yellow foam,which was used in the next step.

[0303]¹H NMR (DMSO-d₆, 400 MHz): δ1.94 (s, 3H), 3.65 (s, 3H), 5.25 (br,2H), 5.97 (br, 2H), 6.36-6.37 (m, 1H), 6.90-6.92 (m, 1H), 6.96-7.06 (m,5H), 7.15-7.23 (m, 2H), 7.26 (s, 1H), 7.32-7.36 (m, 1H), 7.44-7.47 (m,2H). MS [(+)APCI, m/z]: 553[M+H]⁺.

[0304] Anal. Calcd. for C₂₉H₂₃C₁₃N₂O₃+0.13 C₄H₈O₂+O0.13 CH₂C₁₂:C, 61.79,H, 4.25, N, 4.86. Found: C, 60.43, H, 4.50, N, 4.80.

[0305] Step E.10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid

[0306] To a solution of2,2,2-richloro-1-{10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl} ethanone of Step D (2.0 g, 3.6 mmol) inacetone (20 mL) was added 2.5 N sodium hydroxide (2.9 mL, 7.25 mmol).After stirring overnight, the reaction mixture was acidified with 2 Nhydrochloric acid (4.0 mL, 8.0 mmol) then concentrated in vacuo. Theresidue was partitioned between ethyl acetate and water. The organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedin vacuo to give a brown solid. Trituration with diethyl ether-hexaneprovided 1.4 g of the desired product as a white solid, m.p.174-184° C.

[0307]¹H NMR (DMSO-d₆, 400 MHz): δ1.93 (s, 3H), 3.65 (s, 3H), 5.17 (br,2H), 5.94 (br, 2H), Wst:::. 6.09-6.10 (m, 1H), 6.77 (d, 1H), 6.89-7.06(m, 6H), 7.10-7.19 (m, 2H), 7.23 (s, 1H), 7.31-7.38 (m, 2H), 12.31 (br,1H). MS [(−)APCI, m/z]: 451[M−H]⁻.

[0308] Anal. Calcd. for C₂₈H₂₄N₂O₄+0.10 C₄H₁₀O: C, 74.17, H, 5.48, N,6.09. Found: C, 73.63, H, 5.68, N, 5.94.

EXAMPLE 1010-[(3-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid

[0309] Step A. 4-lodo-2-methoxybenzoic acid methyl ester

[0310] 4-Amino-2-methoxybenzoic acid methyl ester (3.0 g, 16.6 mmol) wassuspended in water (40 mL) and concentrated sulfuric acid (10 mL) wasadded. The suspension was cooled in an ice/salt water bath, and anaqueous solution (10 mL) of sodium nitrite (1.26 g, 18.3 mmol) was addeddropwise so that the temperature remained close to 0° C. After theaddition, a homogeneous, yellow-green solution was obtained. An aqueoussolution (60 mL) of potassium iodide (3.02 g, 18.2 mmol) and iodine(2.31 g, 9.1 mmol) was then added dropwise, and the reaction stirred foran additional 1 hour. The reaction mixture was then extracted with ethylacetate, the organic extracts were combined and washed with 1 N sodiumthiosulfate, 1 N sodium hydroxide and brine. After drying over anhydroussodium sulfate the solution was filtered and concentrated in vacuo togive 2.7 g of the title product as an orange oil which was used in thenext step.

[0311]¹H NMR (DMSO-d6, 400 MHz): δ2.76 (s, 3H), 3.82 (s, 3H), 7.39 (s,2H), 7.48 (s, 1H). MS [EI, m/z]: 292[M]⁺.

[0312] Step B. 4-lodo-2-methoxybenzoic acid

[0313] The 4-iodo-2-methoxybenzoic acid methyl ester of Step A (2.7 g,9.24 mmol) was dissolved in tetrahydrofuran (40 mL) and 1 N sodiumhydroxide (20 mL, 20 mmol) was added. The reaction mixture was heated atreflux for 3 hours, then cooled and concentrated in vacuo to give anorange oil that was partitioned between ethyl acetate and 2 Nhydrochloric acid. The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give 2.5 g of titleproduct as a yellow-orange solid, m.p. 144-146° C.

[0314]¹H NMR (DMSO-d6, 400 MHz): δ3.81 (s, 3H), 7.37 (s, 2H), 7.44 (s,1H), 12.72 (br, 1H). MS [EI, m/z]: 278[M]⁺.

[0315] Anal. Calcd. for C₈H₇IO₃₊0.10 C₄H₈O₂: C, 35.17, H, 2.74. Found:C, 35.37, H, 2.49.

[0316] Step C. 10-(4-lodo-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

[0317] A suspension of 4-iodo-2-methoxybenzoic acid of Step B (2.5 g,9.0 mmol) in thionyl chloride (10 mL) was heated at reflux for 1 hour.After cooling, the thionyl chloride was removed in vacuo. The residuewas dissolved in toluene and concentrated in vacuo to give the crudeacid chloride as a brown solid. The acid chloride was then dissolved indichloromethane (10 mL) and slowly added to a solution of 10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine (1.75 g, 9.5 mmol) andN,N-diisopropylethyl amine (3.4 mL, 19.5 mmol) in dichloromethane (20mL). After stirring for 2 hours, the reaction was quenched with water.The organic layer was washed with 1 N hydrochloric acid, 1 N sodiumhydroxide and brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a yellow foam. Purification by flashchromatography on silica gel using a solvent gradient of 15 to 25% ethylacetate in hexane provided 3.6 g of title product as a white foam, whichwas redissolved in dichloromethane and evaporated to dryness prior touse in the next step.

[0318]¹H NMR (DMSO-d₆, 400 MHz): δ3.55 (br, 3H), 4.80-5.32 (br, 4H),5.88-5.90 (m, 1H), 5.94 (s, 1H), 6.79 (s, 1H), 6.94 (s, 1H), 7.03 (t,1H), 7.09-7.13 (m, 3H), 7.20-7.22 (m, 1H), 7.36-7.38 (m, 1H). MS[(+)ESI, m/z]: 445[M+H]⁺.

[0319] Anal. Calcd. for C₂₀H₁₇IN₂O₂+0.10 C₄H₈O₂+0.13 CH₂C₁₂: C, 53.13,H, 3.92, N, 6.04. Found: C, 53.03, H, 3.65, N, 6.03.

[0320] Step D.(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl]-methanone

[0321] A mixture of10-(4-iodo-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step C (1.8 g, 4.1 mmol), 2-methylphenylboronic acid (0.55 g, 4.1 mmol) and sodium carbonate (1.9 g, 17.9 mmol)in toluene:ethanol: water (20 mL:10 mL:10 mL) was purged with nitrogenfor 1 hour. After addition of the tetrakis(triphenylphosphine)palladium(0) catalyst (0.24 g, 0.21 mmol), the reaction mixture washeated at 100° C. overnight. After cooling, the reaction was filteredthrough Celite and the cake washed with ethyl acetate. The organic layerwas washed with water, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a brown oil. Purification by flashchromatography on silica gel using a solvent system of 20% ethyl acetatein hexane provided 1.5 g of title product as a white foam, which wasredissolved in dichloromethane and evaporated to dryness in vacuo priorto use in the next step.

[0322]¹H NMR (DMSO-d₆, 400 MHz): δ2.08 (s, 3H), 3.54 (s, 3H), 4.80-5.30(br, 4H), 5.89-5.91 (m, 1H), 5.97 (s, 1H), 6.66 (s, 1H), 6.77-6.80 (m,2H), 6.93-7.01 (m, 2H), 7.09-7.10 (m, 2H), 7.19-7.24 (m, 3H), 7.36-7.38(m, 2H). MS [(+)ESI, m/z]: 409[M+H]⁺.

[0323] Anal. Calcd. for C₂₇H₂₄N₂O₂+0.10 CH₂C₁₂: C, 78.05, H, 5.84, N,6.72. Found: C, 78.12, H, 5.13, N, 6.69.

[0324] Step E.2,2,2-Trichloro-1-{10-[(3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanoneTo a solution of(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl]-methanoneof Step D (1.36 g, 3.33 mmol) in dichloromethane (15 mL) was addedN,N-diisopropylethyl amine (1.2 mL, 6.89 mmol) followed by slow additionof trichloroacetyl chloride (1.1 mL, 9.85 mmol). The reaction mixturewas stirred overnight at room temperature then was quenched with water.The organic phase was washed with 0.1 N hyrochloric acid followed bywater, then dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a green oil. Purification by flashchromatography on silica gel using a solvent system of 20% ethyl acetatein hexane gave 1.7 g of title product as a yellow foam.

[0325]¹H NMR (DMSO-d₆, 400 MHz): δ2.09 (s, 3H), 3.50 (s, 3H), 5.30 (br,2H), 5.87 (br, 2H), 6.37-6.38 (m, 1H), 6.64 (s, 1H), 6.82-6.83 (m, 1H),6.90-6.92 (m, 1H), 6.97-6.99 (m, 1H), 7.10-7.12 (m, 2H), 7.20-7.25 (m,4H), 7.35-7.37 (m, 1H), 7.44-7.46 (m, 1H). MS [(+)APCI, m/z]: 553[M+H]⁺.

[0326] Anal. Calcd. for C₂₉H₂₃C₁₃N₂O₃+0.20 C₄H₈O₂+0.40 H₂O: C, 61.85, H,4.42, N, 4.84. Found: C, 61.50, H, 4.07, N, 4.72.

[0327] Step F.10-[(3-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid

[0328] To a solution of2,2,2-trichloro-1-{10-[(3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanoneof Step E (1.6 g, 2.9 mmol) in acetone (20 mL) was added 2.5 N sodiumhydroxide (2.3 mL, 5.8 mmol). After stirring overnight, the reaction wasacidified with 2 N hydrochloric acid (3.2 mL, 6.4 mmol) thenconcentrated in vacuo. The residue was partitioned between ethyl acetateand water. The layers were separated, and the organic layer was driedover anhydrous sodium sulfate, filtered and concentrated in vacuo togive a brown solid. Trituration with diethyl ether/hexane provided 1.2 gof desired product as an off-white solid, m.p. 201-204° C.

[0329]¹H NMR (DMSO-d₆, 400 MHz): δ2.09 (s, 3H), 3.48 (s, 3H), 5.20 (br,2H), 5.85 (br, 2H), 6.12 (s, 1H), 6.62 (s, 1H), 6.73 (d, 1H), 6.79-6.87(m, 2H), 6.91-6.95 (m, 1H), 6.99-7.03 (m, 1H), 7.06-7.12 (m, 1H),7.18-7.25 (m, 4H), 7.39 (br, 1H), 12.31 (br, 1H). MS [(+) ESI, m/z]:453[M+Na]⁺.

[0330] Anal. Calcd. for C₂₈H₂₄N₂O₄+0.10 C₄H₁₀O+0.15 C₄H₈O₂: C, 73.61, H,5.58, N, 5.92. Found: C, 73.23, H, 5.49, N, 6.06.

EXAMPLE 11N-Methyl-N-[3-(dimethylamino)propyl]-10-[(3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0331] To a solution of10-[(3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Example 10, Step F (0.40 g, 0.88 mmol),3-(dimethylaminopropyl)-1-methyl amine (0.16 mL, 1.09 mmol) and1-hydroxybenzotriazole (0.135 g, 0.96 mmol) in N,N-dimethylformamide (4mL) was added 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimidehydrochloride (0.19 g, 1.09 mmol) followed by N,N-diisopropylethyl amine(0.24 mL, 1.35 mmol). The reaction mixture was stirred overnight, thendiluted with ethyl acetate and washed with water and saturated aqueoussodium bicarbonate. The organic phase was then dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give a yellowfoam. Purification by flash chromatography on silica gel using a solventsystem of 5% methanol in dichloromethane afforded 0.36 g of titlecompound as a white foam.

[0332]¹H NMR (DMSO-dr, 400 MHz): δ1.67-1.73 (m, 2H), 2.08-2.25 (m, 1OH),3.03 (s, 3H), 3.45-3.50 (m, 6H), 4.60-5.40 (br m, 4H), 6.05-6.06 (m,1H), 6.25-6.26 (m, 1H), 6.62 (s, 1H), 6.79-6.81 (m, 1H), 6.85-6.87 (m,1H), 6.91-6.95 (m, 1H), 7.03-7.06 (m, 1H), 7.09-7.11 (m, 1H), 7.19-7.30(m, 4H), 7.38 (br, 1H). MS [(+)ESI, m/z]: 551[M+H]⁺.

[0333] Anal. Calcd. for C₃₄H₃₈N₄O₃+0.20 H₂O: C, 73.67, H, 6.98, N,10.11. Found: C, 73.50, H 7.08, N, 9.96.

EXAMPLE 12 7,8-Dimethoxy-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl][2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]methanone

[0334] Step A.1-[(4,5-Dimethoxy-2-nitrophenyl)methyl]-1H-pyrrole-2-carboxaldehyde

[0335] To a suspension of sodium hydride (0.724 g, 60% suspension inoil) in N,N -dimethyl formamide (50 mL) was added pyrrole2-carboxaldehyde (1.7 g, 18.1 mmol) and the reaction mixture was stirredfor 30 minutes. It was then cooled to 0° C. and4,5-dimethoxy-2-nitrobenzyl bromide (5.0 g, 1 equiv) was added dropwiseover 20 minutes. After the addition, the reaction mixture was stirred atroom temperature for 3 hours. It was then diluted with ethyl acetate(450 mL), washed with water, dried over anhydrous magnesium sulfate,filtered and evaporated to dryness. The crude product was trituratedwith water, filtered and washed with water. This material was dried overanhydrous potassium carbonate in vacuo to provide the title compound asa yellow crystalline solid (4.97 g), m.p. 109-112° C., which was used inthe next step.

[0336] Step B. 7,8-Dimethoxy-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

[0337] A mixture of the1-[(4,5-dimethoxy-2-nitrophenyl)methyl]-1H-pyrrole-2-carboxaldehyde ofStep A (4.97 g), acetic acid (0.5 mL), magnesium sulfate (0.5 g) and 10%palladium on charcoal (0.5 g) in ethyl acetate (50 mL) was hydrogenatedovernight at atmospheric pressure. The reaction was then filteredthrough Celite and the solvent removed in vacuo to give the crude titlecompound as an amber foam (3.2 g) which was used in the next stepwithout further purification.

[0338] Step C. 7,8-Dimethoxy-(10,11-dihydro-5H-pyrrolo[2,1-c[1,4]benzodiazepin-10-yl)-(4-bromo-3-methyl-phenyl)-methanone

[0339] To a solution of 7,8-dimethoxy-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step B (3.20 g) in dichloromethane (20 mL)was added 3-methylbenzoyl chloride (3.4 g, 1.1 equiv) and triethylamine(2.0 9, 1.5 equiv) and the mixture was stirred at room temperatureovernight. The solvent was then removed in vacuo and the residuechromatographed on silica gel eluting with a solvent gradient from 5 to50% of ethyl acetate in petroleum ether to provide the title compoundsas a yellow crystalline solid (3.5 g), m.p. 165-168° C.

[0340]¹H NMR (CDCl₃, 200 MHz): δ2.30 (s, 3H), 3.55 (br, 3H), 3.85 (s,3H), 5.1 (br, 4H), 6.05 (br, 1H), 6.1 (t, 1H), 6.3 (br, 1H), 6.65 (t,1H), 6.8 (s, 2H), 7.3 (s, 2H). MS [(+)ESI, m/z]: 442[M +H]⁺.

[0341] Step D. 7,8-Dimethoxy-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl][2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanone

[0342] The 7,8-dimethoxy-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl) -(4-bromo-3-methyl-phenyl)-methanone ofStep C (1.0 g) was reacted with 2-trifluoromethylphenyl boronic acid(0.645 g, 1.5 equiv.), potassium phosphate (0.964 g, 2.0 equiv.) and acatalytic amount (0.050 g) of tetrakis(triphenylphosphine) palladium(0)in refluxing dioxane (10 mL) under nitrogen for 24 hours. The reactionwas then cooled to room temperature, filtered through Celite, and thesolvent removed in vacuo. The residue was dissolved in dichloromethaneand the solution was washed with water, dried over anhydrous magnesiumsulfate, filtered and evaporated to dryness. The crude product soobtained was purified by chromatography on silica gel eluting with 5%ethyl acetate/dichloromethane to provide the title product (1.0 g) as awhite crystalline solid, m.p. 187-188° C.

[0343]¹H NMR (DMSO-d₆, 400 MHz): δ1.85 (s, 3H), 3.40 (s, 3H), 3.70 (s,3H), 5.20 (br, 4H), 5.92 (t, 1H), 5.96 (s, 1H), 6.56 (s, 1H), 6.77 (t,1H), 6.90 (m, 1H), 7.05 (m, 2H), 7.20 (d, 1H), 7.30 (s, 1H), 7.58 (t,1H), 7.68 (t, 1H), 7.80 (d, 1H). MS [(+)APCI, m/z]: 507[M+H]⁺.

[0344] Anal. Calcd. for C₂₉H₂₅F₃N₂O₃: C, 68.77, H, 4.97, N, 5.53. Found:C, 68.85, H, 5.05, N 5.43.

EXAMPLE 13N-Methyl-[N-(3-dimethylamino)propyl]-7,8-dimethoxy-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide hydrochloride salt

[0345] A solution of the 7,8-dimethoxy-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl][2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]methanoneof Example 12, Step D (0.31 mmol), diphosgene (1.1 equiv.) andtriethylamine (1.5 equiv.) in dichloromethane (5 mL) was stirred at roomtemperature overnight. The solvent was removed in vacuo and the residuewas dissolved in dichloromethane (5 mL). To the solution was addedtriethylamine (1.5 equiv.) and 3-(dimethylaminopropyl)-1-methyl amine(1.5 equiv.). The reaction mixture was then washed with water, driedover anhydrous magnesium sulfate, filtered and evaporated to dryness.The residue was first chromatographed on silica gel eluting with asolvent gradient from 2 to 5% of methanol in dichloromethane and thenchromatographed again with solvent gradient from 2 to 5% of methanol inethyl acetate to provide the title compound (0.100 g) as a colorlessfoam. Treatment of a solution of the free base in ethanol with anhydroushydrogen chloride in dioxane followed by removal of the solvent providedthe hydrochloride salt as a brown solid, m.p. 118° C.

[0346]¹H NMR (DMSO-d₆, 400 MHz): δ1.85 (s, 3H), 2.00 (m, 2H), 3.05 (t,2H), 2.75 (s, 6H), 3.10 (s, 3H), 3.40 (s, 3H), 3.55 (t, 2H), 3.70 (s,3H), 5.30 (s, 4H), 6.05 (s, 1H), 6.35 (d, 1H), 6.50 (s, 1H), 6.90 (s,1H), 6.95 (s, 2H), 7.20 (d, 1H), 7.30 (s, 1H), 7.60 (t, 1H), 7.70 (t,1H), 7.80 (d, 1H), 10.25 (br, 1H). MS [(+)ESI, m/z]: 649[M+H]⁺.

[0347] Anal. Calcd. For C₃6H₃₉F₃N₄O₄+HCl +2H₂O: C, 59.95, H, 6.15, N,7.77. Found: C, 59.40, H, 6.63, N, 7.86.

EXAMPLE 147,8-Dimethoxy-10-{[2-methyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl]carbonyl}-[(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]-4-piperidinone

[0348] A solution of the 7,8-dimethoxy-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl][2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanoneof Example 12, Step D (0.31 mmol), diphosgene (1.1 equiv.) andtriethylamine (1.5 equiv.) in dichloromethane (5 mL) was stirred at roomtemperature overnight. The solvent was removed in vacuo, the residue wasdissolved in dichloromethane (5 mL), and then triethylamine (1.5 equiv.)and 4-piperidone (1.5 equiv.) were added. The reaction mixture wasstirred overnight, washed with water, dried over anhydrous magnesiumsulfate, filtered and evaporated to dryness. The residue was firstchromatographed on silica gel eluting with 2% methanol indichloromethane and then chromatographed again with 2% methanol in ethylacetate to provide the title compound as a yellow solid, m.p. 132-134°C.

[0349]¹H NMR (DMSO-d₆, 400 MHz): δ1.85 (s, 3H), 2.45 (m, 4H), 3.40 (s,3H), 3.65 (s, 3H), 3.90 (t, 4H), 5.20 (br, 2H), 5.35 (s, 2H), 6.10 (s,1H), 6.40 (d, 1H), 6.50 (s, 1H), 6.90 (s, 1H), 7.00 (s, 1H), 7.05 (s,1H), 7.20 (d, 1H), 7.30 (s, 1H), 7.60 (t, 1H), 7.65 (t, 1H), 7.80 (d,1H). MS [(+)APCI, m/z]: 632[M+H]⁺.

[0350] Anal. Calcd. for C₃₅H₃₂F₃N₃O₅+H₂O: C, 64.71, H, 5.38, N, 6.47.Found: C, 65.20, H, 5.12, N, 6.41.

EXAMPLE 1510-{[6-Chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid

[0351] Step A. 4-lodo-5-chloro-2-methoxy benzoic acid

[0352] A stirred solution of 4-amino-5-chloro-2-methoxy benzoic acid(12.25 g , 60.8 mmol) in water (136 mL ) and concentrated sulfuric acid(34 mL) was cooled to 0° C. in a flask fitted with an overhead stirrer.A solution of sodium nitrite (4.62 g , 66.9 mmol) in water (26 mL) wasadded dropwise while keeping the internal temperature around 0° C.

[0353] Potassium iodide (11.11 g , 66.9 mmol) and iodine (4.246g , 33.5mmol) were dissolved in water (130 mL) and added dropwise to the stirredreaction mixture. After 2 hours the reaction was extracted with ethylacetate. The organic extracts were then washed with 10% sodiumthiosulfate and brine, then dried over magnesium sulfate, filtered andevaporated to dryness to yield 11.32 g of the title compound, m.p.150-1510C. This material was used in the next step without furtherpurification.

[0354]¹H NMR (DMSO-d₆, 400 MHz): δ13.03 (br, 1H), 7.70 (s, 1H), 7.63 (s,1H), 3.82 (s, 3H). MS [(−)-APCI, m/z]: 311[M -H]⁻.

[0355] Anal. Calcd. for C₈H₆CIIO₃: C, 30.75, H, 1.94. Found: C, 31.28,H, 1.78.

[0356] Step B.2-Chloro-2′-trifluoromethyl-5-methoxy[1,1′-biphenyl]-4-carboxylic acid.

[0357] To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acidof Step A (3.12 g, 10 mmol) in N,N-dimethylformamide (100 mL) was added2-trifluoromethyl phenyl boronic acid (5.70 g, 30 mmol) and potassiumcarbonate (12.73 g, 92 mmol). This mixture was purged with nitrogen andthen treated with tetrakis(triphenylphosphine) palladium(0) (0.58 g, 0.5mmol). The reaction was heated to reflux overnight, cooled, acidifiedwith 2 N hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous magnesium sulfate,filtered, and evaporated to provide a nearly quantitative amount of thetitle acid which was used in the next step without further purification.

[0358] Step C.10-{[6-Chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

[0359] A stirred solution of the 2-chloro-2′-trifluoromethyl-5-methoxy[1,1′-biphenyl]-4-carboxylic acid of Step B (3.46 g, 10.46 mmol) intetrahydrofuran (20 mL) containing a catalytic amount ofN,N-dimethylformamide was treated dropwise with thionyl chloride (1.36g, 11.51 mmol). The reaction mixture was stirred for 2 hours, and thenadded dropwise to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.92 g 10.46 mmol) in tetrahydrofuran (20mL) containing triethylamine (2.32 g, 23 mmol). The reaction mixture wasstirred for 2 hours, diluted with dichloromethane and washed withsaturated aqueous sodium bicarbonate and brine. The organic layer wasdried over anhydrous magnesium sulfate, filtered, and evaporated todryness. Trituration of the residue with acetone gave the title compound(3.14 g). Recrystallization from acetone/hexanes provided whitecrystals, m.p. 208-210OC;

[0360]¹H NMR (DMSO-d₆, 400 MHz) 8 3.46 (s, 3H), 5.16-5.20 (br d, 3H),5.89 (t, 1H), 5.97 (s, 1H), 6.70 (s, 1H), 6.80 (t, 1H), 7.80-7.00 (m, 1OH); MS [(+) ESI, m/z]: 497[M+H]⁺.

[0361] Anal. Calcd. for C₂₇H₂₀CIF₃N₂O₂+0.5 H₂O: C, 64.10, H, 4.18, N,5.54. Found: C, 64.40, H, 3.97, N, 5.54.

[0362] Step D.10-{[6-Chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid

[0363] A solution of the10-{[6-chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step C (2.29 g, 4.6 mmol) indichloromethane (30 mL) was treated with N,N-diisopropylethyl amine(0.62 g, 4.84 mmol) and stirred for 10 minutes. Trichloroacetyl chloride(0.92 g, 5.07 mmol) was then added dropwise. The reaction mixture wasstirred overnight, diluted with dichloromethane, washed with 0.1 Nhydrochloric acid, saturated aqueous sodium bicarbonate, and brine. Theorganic phase was dried over anhydrous magnesium sulfate, filtered, andevaporated to yield the crude trichloroketone intermediate which withoutfurther purification, was dissolved in acetone and treated with anexcess of 1 N sodium hydroxide. The mixture was stirred overnight, andthen diluted with isopropyl acetate and acidified with 1 N hydrochloricacid. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate, filtered, and evaporated to dryness. The solidresidue was triturated with methanol to provide the title compound(1.23g ) as a white solid, m.p. 220-222° C. (dec).

[0364]¹H NMR (DMSO-d₈, 400 MHz) 8 3.40 (s, 3H), 6.12 (d, 1H), 6.68 (s,1H), 6.72 (d, 1H), 6.94 (s, 2H), 7.07 (t, 1H), 7.25 (d, 2H), 7.62 (t,2H), 7.70 (t, 1H), 7.78 (d, 1H), 12.31 (br, 1H). MS [(+)APCI, m/z]:541[M+H]⁺.

[0365] Anal. Calcd. for C₂₈H₂₀CIF₃N₂O₄+0.25 H₂O: C, 61.66, H, 3.79, N,5.14. Found: C, 61.47, H, 3.64, N, 5.06.

EXAMPLE 1610{[2′-Chloro-6-chloro-3-methoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid

[0366] Step A. 2′-Chloro-2-chloro-5-methoxy-[1,1′-biphenyl]-4-carboxylicacid.

[0367] To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acid(3.12 g, 10 mmol) in N,N-dimethylformamide (100 mL) was added 2-chlorophenyl boronic acid (5.07 g, 32.4 mmol) and potassium carbonate (12.73g, 92 mmol). This mixture was purged with nitrogen and then treated withtetrakis(triphenylphosphine) palladium(0) (0.58 g, 0.5 mmol). Thereaction was heated to reflux overnight, cooled, acidified with 2 Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous magnesium sulfate, filtered,and evaporated to provide a nearly quantitative amount of the title acidwhich was used in the next step without further purification.

[0368] Step B.10-{[2′-Chloro-6-chloro-3-methoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine

[0369] A stirred solution of the2′-chloro-2-chloro-5-methoxy-[1,1′-biphenyl]-4-carboxylic acid of Step A(3.09 g, 10.46 mmol) in tetrahydrofuran (20 mL) containing a catalyticamount of N,N-dimethylformamide was treated dropwise with thionylchloride (1.36 g, 11.51 mmol). The reaction mixture was stirred for 2hours, and then added dropwise to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.92 g 10.46 mmol) in tetrahydrofuran (20mL) containing triethylamine (2.32 g, 23 mmol). The reaction mixture wasstirred for 2 hours, diluted with dichloromethane and washed withsaturated aqueous sodium bicarbonate and brine. The organic layer wasdried over anhydrous magnesium sulfate, filtered, and evaporated todryness. Trituration of the residue with ethyl acetate gave the titlecompound (1.93 g) which was recrystallized from ethyl acetate/hexanes aswhite crystals, m.p. 209-211° C.;

[0370]¹H NMR (DMSO-d₆, 400 MHz) 8 3.55 (s, 3H), 5.16-5.20 (br m, 3H),5.89 (t, 1H), 5.97 (s, 1H), 6.71 (s, 1H), 6.80 (s, 1H), 7.04-7.60 (m,1OH). MS [(+) APCI, m/z]: 463[M+H]⁺.

[0371] Anal. Calcd. for C₂₆H₂₀C₁₂N₂O₂+0.25 C₄H₈O₂: C, 66.81, H, 4.57, N,5.77. Found: C 66.76, H, 4.24, N, 5.93.

[0372] Step C.10-{[2′-Chloro-6-chloro-3-methoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid

[0373] A solution of10-{[2′-chloro-6-chloro-3-methoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step B (2.1 g, 4.6 mmol) indichloromethane (30 mL) was treated with N,N-diisopropylethyl amine(0.62 g, 4.84 mmol) and stirred for 10 minutes. Trichloroacetyl chloride(0.92 g, 5.07 mmol) was then added dropwise. The reaction mixture wasstirred overnight, diluted with dichloromethane, washed with 0.1 Nhydrochloric acid, saturated aqueous sodium bicarbonate, and brine. Theorganic phase was dried over anhydrous magnesium sulfate, filtered, andevaporated to yield the crude trichloroketone intermediate which withoutfurther purification, was dissolved in acetone and treated with anexcess of 1 N sodium hydroxide. The mixture was stirred overnight,diluted with isopropyl acetate and acidified with 1 N hydrochloric acid.The organic layer was washed with brine, dried over anhydrous magnesiumsulfate, filtered, and evaporated to dryness. The solid residue wastriturated with methanol to provide the title compound as a white solid,which was used without further purification.

EXAMPLE 1710-{[6-Chloro-3-methoxy-2′-ethoxyt1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

[0374] Step A. 2-Chloro-2′-ethoxy-5-methoxy [1,1′-biphenyl]-4-carboxylicacid

[0375] To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acidof Example 15, Step A (0.500 g, 1.6 mmol) in N,N-dimethylformamide (30mL) was added 2-ethoxy phenyl boronic acid (0.8 g, 4.8 mmol) andpotassium carbonate (2.04 g, 14.7 mmol). This mixture was purged withnitrogen and then treated with a catalytic amount of tetrakis(triphenylphosphine) palladium(0) (0.093 g, 0.08 mmol). The reaction washeated to reflux overnight, cooled, acidified with 2 N hydrochloric acidand extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate, filtered, and evaporatedto yield the title acid which was used in the next step without furtherpurification.

[0376] Step B.10-{[6-Chloro-3-methoxy-2′-ethoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine

[0377] To a stirred solution of the 2-chloro-2′-ethoxy-5-methoxy[1,1′-biphenyl]-4-carboxylic acid of Step A (0.491 g) in tetrahydrofuran(5 mL) containing a catalytic amount of N,N-dimethyl formamide was addeddropwise thionyl chloride (0.210 g, 1.76 mmol). The reaction mixture wasstirred for 2 hours, and then added dropwise to a solution of10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine (0.294 g, 1.60 mmol)in tetrahydrofuran (5 mL) containing triethylamine (0.357 g, 3.52 mmol).The reaction mixture was stirred for 2 hours, diluted withdichloromethane and washed with saturated aqueous sodium bicarbonate andbrine. The organic layer was dried over anhydrous magnesium sulfate,filtered, and evaporated to dryness. Trituration of the residue withmethanol provided the title compound as an off-white solid, 99.24% pureby analytical HPLC [Primesphere C-18 column (2.0×150 mm); mobile phase70/30 acetonitrile/water containing 0.1% phosphoric acid], m.p. 213-215°C.

[0378]¹H NMR (DMSO-d₆, 400 MHz): 5 1.11, (t, 3H), 3.51 (s, 3H), 3.92 (q,2H), 5.17-5.20 (br, m, 3H), 5.89 (t, 1H), 5.97 (s, 1H), 6.67-7.55 (m,1OH). MS [(+)APCI, m/z]: 473[M+H]⁺.

[0379] Anal. Calcd. for C₂₈H₂₅CIN₂O₃: C, 71.11, H, 5.33, N, 5.92. Found:C, 70.31, H, 5.27, N 5.79.

EXAMPLE 1810-{[6-Chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid

[0380] Step A. 2-Chloro-2′-fluoro-5-methoxy[1,1′-biphenyl]-4-carboxylicacid

[0381] To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acidof Example 15, Step A (3.72 g, 19.1 mmol) in N,N-dimethylformamide (20mL) was added 2-fluoro phenyl boronic acid (5.0 g, 35.7 mmol) andpotassium carbonate (14.8 g, 107 mmol). This mixture was purged withnitrogen and then treated with a catalytic amount of tetrakis(triphenylphosphine) palladium(0) (0.688 g, 0.59 mmol). The reaction washeated to reflux overnight, cooled, acidified with 2 N hydrochloric acidand extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate, filtered, and evaporatedto dryness. The residue was flash chromatographed on acid washed silicausing a 10 to 50% gradient of diethyl ether in hexane to provide thedesired title compound (3.8 g) as a white solid.

[0382]¹H NMR (DMSO-d₆1,400 MHz) 6 3.83 (s, 3H), 7.15 (s, 1H), 7.30-7.35(m, 2H), 7.42 (m, 1H), 7.48-7.54 (m, 1H), 7.74 (s, 1H). MS [(+)ESI,m/z]: 298[M+NH₄]⁺.

[0383] Anal. Calcd. for C₁₄H₁₀CIFO₃: C, 59.91, H, 3.59. Found: C, 59.79,H, 3.35.

[0384] Step B.10-{[6-Chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine

[0385] To a stirred solution of2-chloro-2′-fluoro-5-methoxy[1,1′-biphenyl]-4-carboxylic acid of Step A(3.80 g, 13.5 mmol) in tetrahydrofuran (20 mL) containing a catalyticamount of N,N-dimethylformamide was added dropwise thionyl chloride(1.77 g, 14.9 mmol). The reaction mixture was stirred for 2 hours, andthen added dropwise to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (2.49 g, 13.5 mmol) in tetrahydrofuran (20mL) containing triethylamine (3.0 g, 29.8 mmol). The reaction mixturewas stirred for 2 hours, diluted with dichloromethane and washed withsaturated aqueous sodium bicarbonate and brine. The organic layer wasdried over anhydrous magnesium sulfate, filtered, and evaporated todryness. Recrystallization of the residue from ethyl acetate/heptaneprovided the title compound as a pale yellow solid, m.p. 192-194° C.,found to be 99.99% pure by analytical HPLC [Primesphere C-18 column(2.0×150 mm); mobile phase: gradientfrom 10 to 100% ofacetonitrile/water containing 0.1% phosphoric acid, 7 minute gradient].

[0386]¹H NMR (DMSO-d₆, 400 MHz) 6 3.55 (s, 3H), 5.19 (br m, 2H), 5.90(t, 1H), 5.96 (s, 1H), 6.80 (s, 2H), 7.07-7.63 (m, 1OH). MS [(+)ESI,m/z]: 447[M+H]⁺.

[0387] Anal. Calcd. for C₂₆H₂₀CIFN₂O₂+H₂O: C, 69.60, H, 4.54, N, 6.24.Found: C, 69.39, H, 4.41, N, 6.20.

[0388] Step C.10-{[6-Chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid

[0389] A solution of the10-{[6-chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step B (3.02 g, 6.76 mmol) indichloromethane (35 mL) was treated with N,N-diisopropylethyl amine(0.960 g, 7.43 mmol) and stirred for 10 minutes. Trichloroacetylchloride (1.47 g, 8.10 mmol) was then added dropwise. The reactionmixture was stirred overnight, diluted with dichloromethane, washed with0.1 N hydrochloric acid, saturated aqueous sodium bicarbonate, andbrine. The organic phase was dried over anhydrous magnesium sulfate,filtered, and evaporated to yield the crude trichloroketone intermediatewhich without further purification, was dissolved in acetone and treatedwith an excess of 1 N sodium hydroxide The mixture was stirredovernight, and then diluted with isopropyl acetate and acidified with 1N hydrochloric acid. The organic layer was washed with brine, dried overanhydrous magnesium sulfate, filtered, and evaporated to dryness. Thesolid residue was triturated with methanol to provide the title compound(2.95 g) as a beige solid, m.p. 207-208° C.

[0390]¹H NMR (DMSO-d₆, 400 MHz) 6 3.49 (br, 3H), 6.12 (d, 1H), 6.72 (d,1H), 6.77 (s, 1H), 7.01 (d, 2H), 7.09 (m, 1H), 7.26 (m, 4H), 7.45 (m,2H), 7.61 (br, 1H), 12.35 (br, 1H). MS [(+)APCI, m/z]: 491[M+H]⁺.

[0391] Anal. Calcd for C₂₇H₂₀CIFN₂O₄: C, 66.06, H, 4.11, N, 5.71. Found:C, 65.68, H, 4.24, N 5.48.

EXAMPLE 1910-{[2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid

[0392] Step A. Trifluoromethanesulfonic acid 4-formyl-2-methoxy-phenylester

[0393] To a solution of vanillin (6.08 g, 40.0 mmol) and triethylamine(6.70 mL, 48.0 mmol) in dichloromethane (300 mL) was added dropwise asolution of trifluoromethane sulfonic anhydride (12.4 g, 44.0 mmol) indichloromethane (100 mL) at 0° C. After stirring for 2 hours, thesolution was concentrated, and the residue washed with water andextracted twice with ethyl acetate. Upon drying and concentrating, theresidual dark oil was subjected to flash chromatography on silica geleluting with 20% ethyl acetate in hexane providing the title product(8.91 g) as a light yellow oil, which was used in the next step withoutfurther purification.

[0394] Step B.2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxaldehyde

[0395] A stirred solution of trifluoromethanesulfonic acid4-formyl-2-methoxy-phenyl ester of Step A (6.9 g, 22.1 mmol),2-trifluoromethyl phenyl boronic acid (5.4 g, 28.6 mmol) and potassiumphosphate (13.2 g, 62.2 mmol) in N,N-dimethylformamide (120 mL) wasdegassed with nitrogen, whereupon a catalytic amount (0.285 g) of[1,4-bis -(diphenylphosphine)butane]palladium (II) dichloride was added.The solution was heated to 120° C. for 5 hours, poured into water andextracted with ethyl acetate. The combined extracts were washed withwater, dried over anhydrous magnesium sulfate and filtered through aplug of silica gel. Removal of the solvent provided the crude titlecompound (4.54 g) as an oil, which was used as such in the next step.

[0396]¹H NMR (200 MHz, CDCl₃): δ10.03 (s, 1H), 8.14 (d, 1H), 7.31-7.56(m, 6H), 3.91 (s, 3H).

[0397] Step C. 2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylicacid

[0398] The 2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxaldehydeof Step B (0.95 9, 3.41 mmol) and sulfamic acid (0.43 g, 4.43 mmol) weredissolved in a mixture of tetrahydrofuran and water (1:1, v/v, 30 mL).Sodium chlorite (0.31 g, 4.43 mmol) was added under stirring, and thesolution turned yellow. After 30 minutes, additional sodium chlorite andsulfamic acid were added, and the solution stirred an additional hour.The solution was then concentrated, and the residue partitioned betweenethyl acetate and water. The ethyl acetate layer was dried andconcentrated to yield an oil, which solidified upon trituration withhexane to provide the title compound (0.84 9) as a yellow solid, whichwas used in the next step.

[0399] Step D. (10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-methanone

[0400] The 2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylicacid of step C (1.6 g, 5.40 mmol) was added to a flask containingtoluene (30 mL), thionyl chloride (1.4 mL) and one drop ofN,N-dimethylformamide. The solution was stirred at 70° C. for 1 hour andthen concentrated in vacuo. The residue was diluted with dichloromethane(40 mL) and to this solution was added 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.94 9, 5.16 mmol). After the solutionbecame homogeneous, N,N-diisopropylethyl amine (1.07 mL, 6.19 mmol) wasadded in one portion at 0° C. After 30 minutes the solution wasconcentrated, and the residue partitioned between water and ethylacetate. The ethyl acetate was dried and concentrated to give a crudeoil, which was chromatographed on silica gel eluting with 30% ethylacetate in hexane to yield 1.2 g of product. The solid wasrecrystallized from ethyl acetate/hexane to provide the desired titleproduct (0.87 g) as colorless crystals, m.p. 146-148° C.

[0401]¹H NMR (400 MHz, DMSO-d₆) 6 7.72 (d, 1H), 7.62 (t, 1H ), 7.53 (t,1H), 7.46 (d, 1H), 7.19 (m, 2H), 7.11 (t, 1H), 6.92-7.01 (m, 4H), 6.83(s, 1H), 5.95 ( bs, 1H), 5.91 (s, 1H), 5.31 (br, 4H), 3.45 (s, 3H). MS[(+)ESI, m/z]: 463[M+H]⁺.

[0402] Anal. Calcd. for C₂₇H₂₁F₃N₂O₂: C, 70.12, H, 4.58, N, 6.06. Found:C, 70.53, H, 4.72, N, 5.89.

[0403] Step E.10-{[2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid

[0404] To a stirred solution of the (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-methanone ofStep D (2.34 g, 5.0 mmol) and N,N-diisopropylethyl amine (1.04 mL, 6.0mmol) in dichloromethane (100 mL) was added dropwise a solution oftrichloroacetyl chloride (1.09 g, 6.0 mmol) in dichloromethane (20 mL)kept at 0° C. After the addition was complete, the solution was stirredovernight at room temperature, then washed with 10% aqueous potassiumcarbonate. The organic phase was dried and concentrated to yield a blackresidue. The residue was purified by filtration through a plug of silicagel, eluting with 20% ethyl acetate in hexane. The resulting tan coloredproduct was dissolved in acetone and 1 N sodium hydroxide (2:1, v/v) andthe mixture was stirred for 30 minutes. The solution was thenconcentrated and extracted with ethyl acetate. The combined organicphases were dried and concentrated to yield a yellow oil. The oil wastriturated with hexane, and the resulting solid was removed byfiltration to yield the title compound (1.86 g) as an off white solid,which was used without further purification.

EXAMPLE 20{[10-(2-Methoxy)-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-[(2S)-[(2-pyrrolidin-1-yl)methyl]pyrrolidin-1-yl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl-methanone

[0405] To a stirred solution of the10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 19 (0.230 g, 0.5mmol) in N,N-dimethylformamide (15 mL), was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.120 g,0.625 mmol) and 1-hydroxybenzotriazole (0.087 g, 0.625 mmol). After thesolution became homogeneous,(S)-(+)-1-[(2-pyrrolidin-1-yl)methyl]-pyrrolidine (0.100 g, 0.625 mmol)was added, and the mixture was stirred at room temperature overnight.The solution was then poured into water and extracted with ethylacetate. The combined ethyl acetate layers were washed with water, driedover anhydrous sodium sulfate and concentrated to dryness. The residuewas subjected to silica chromatography eluting with 5% methanol inchloroform. The pure fractions were concentrated and the residuetriturated several times with hexane to provide the title product (0.120g) as a white solid, m.p. 125-128° C.

[0406]¹H NMR (400 MHz, DMSO-d₆): 67.74 (d, 1H), 7.62 (t, 1H ), 7.56(t,IH), 7.38 (m, 1H), 7.19 (d, 1H), 7.11 (t, 1H), 7.04 (t, 1H),6.85-6.973 (m, 4H), 6.40 (s, 1H), 6.06 (s, 1H), 5.62 (br, 1H), 5.46 (br,1H), 4.35 (br, 1H), 3.57 (m, 2H), 1.4-1.98 (m, 8H). MS [EI, m/z]:642[M]⁺.

[0407] Anal. Calcd. for C₃₇H₃₇F₃N₄O₃+0.5 H₂O: C, 68.19, H, 5.88, N,8.60. Found: C, 68.38, H 6.15, N, 8.20.

EXAMPLE 21N-Methyl-[N-(3-dimethylamino)propyl]-10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-carboxamide

[0408] The title compound (white solid, m.p. 140-142° C.) was preparedby coupling the10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 19, with3-(dimethylamino)propyl-1-methylamine (1.25 equiv), in the manner ofExample 20.

[0409]¹H NMR (400 MHz, DMSO-d₆): δ1.65 (m, 2H), 2.05-2.21 (m, 8H), 3.06(s, 3H), 3.42 (s, 3H), 3.44 (t, 2H), 5.20 (br, 2H), 5.44 ( br, 2H), 6.06(s, 1H), 6.23 (s, 1H), 6.85-6.97 (m, 4H), 7.04 (t, 1H), 7.11 (t, 1H),7.19 (d, 1H), 7.38 (d, 1H), 7.56 (t, 1H), 7.62 (t, 1H), 7.74 (d, 1H). MS[EI, m/z]: 604[M]⁺.

[0410] Anal. Calcd. for C₃₄H₃₅F₃N₄O₃: C, 67.54, H, 5.83, N, 9.27. Found:C, 67.15, H, 5.82, N, 9.20.

EXAMPLE 22N-Methyl-[N-(2-dimethylamino)ethyl]-10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0411] The title compound (white solid, 0.149 g, m.p. 187-190° C.) wasprepared by coupling the10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 19, with3-(dimethylamino)ethyl-1-methyl amine (1.25 equiv), in the manner ofExample 20.

[0412]¹H NMR (400 MHz, DMSO-d₆): δ3.06 (s, 3H), 3.42 (m, 5H), 3.84 (t,2H), 5.54 ( br, 2H), 6.06 (s, 1H), 6.42 (s, 1H), 6.85-6.97 (m, 4H), 7.04(t, 1H), 7.11 (t, 1H), 7.19 (m, 2H), 7.38 (d, 1H), 7.56 (t, 1H), 7.62(t, 1H), 7.74 (d, 1H). MS [EI, m/z]: 590[M+.

[0413] Anal. Calcd. for C₃₃H₃₃F₃N₄O₃: C, 63.21, H, 5.46, N, 8.93. Found:C, 62.15, H, 5.59, N, 8.28.

EXAMPLE 23 [4-(Naphtalen-1-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

[0414] Step A. 4-Naphthalen-1-yl-benzoic acid methyl ester

[0415] Methyl 4-bromobenzoate (0.96 g, 4.46 mmol) was added to a mixtureof 1-naphthaleneboronic acid (0.73 g, 4.25 mmol) and sodium carbonate(0.075 g, 7.08 mmol) in toluene (30 mL), ethanol (6 mL) and water (12mL). The resultant solution was purged with nitrogen for 10 minutesbefore tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.09 mmol) wasadded. The reaction mixture was heated to reflux for 65 hours. Thesolution was cooled to ambient temperature, then filtered through a padof Celite, which was subsequently rinsed with ethyl acetate. Thecombined filtrate was diluted to 100 mL with water/ethyl acetate (1:1).The aqueous layer was extracted with ethyl acetate, and the combinedextracts were dried over anhydrous magnesium sulfate, filtered, andevaporated to dryness to yield the title compound as a gold oil (1.09g). This material was used without further purification in the nextstep.

[0416]¹H NMR (300MHz, DMSO-d₆): 63.92 (s, 3H), 7.57 (m, 6H), 7.75 (d,1H), 8.02 (t, 2H), 8.10 (d, 2H).

[0417] Step B. 4-Naphthalen-1-yl-benzoic acid

[0418] To a stirred solution of the 4-naphthalen-1-yl-benzoic acidmethyl ester of Step A (1.09 g, 4.15 mmol) in methanol (18 mL) and water(6 mL), cooled to 5° C., was added lithium hydroxide monohydrate (0.42g, 10.0 mmol). The solution was allowed to warm to ambient temperatureas stirring was continued for 20 hours. The reaction mixture was pouredinto water, acidified to pH, 4 with acetic acid, and the resultantprecipitate was isolated by vacuum filtration to afford the titlecompound as an off-white solid (0.92 g), m.p. 221-224° C.

[0419]¹H NMR (400MHz, DMSO-d6): 66.40-7.60 (m, 6H), 7.56 (d, 1H), 7.98(d, 1H), 8.01 (d, 1H), 8.07 (d, 2H). MS [EI, m/z]: 248[M]⁺.

[0420] Anal. Calc'd. for C₁₇H₁₂O₂: C, 82.24, H, 4.87. Found: C, 81.90,H, 4.63.

[0421] Step C. [4-(Naphtalen-1-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin -10-yl]methanone

[0422] N,N-Dimethylformamide (2 drops) was added to a solution of the4-naphthalen-1-yl-benzoic acid of Step B (0.60 g, 2.40 mmol), inanhydrous tetrahydrofuran (15 mL) followed by oxalyl chloride (0.34 g,2.64 mmol) and the mixture was warmed to reflux. The resultant solutionwas cooled to ambient temperature before being evaporated to dryness togive the crude acid chloride as a gold solid, which was used withoutfurther purification. To a mixture of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.37 g, 2.00 mmol) and triethylamine (0.24g, 2.40 mmol) in dichloromethane (5 mL), cooled in an ice bath, wasadded dropwise a solution of the crude acid chloride in dichloromethane(5 mL). The cooling bath was removed and after stirring for 48 hours,the reaction mixture was washed sequentially with water, saturatedaqueous sodium bicarbonate, saturated aqueous sodium chloride and 1 Nsodium hydroxide. The dichloromethane solution was dried with anhydrousmagnesium sulfate, filtered, then evaporated to dryness to yield a brownfoam. Purification by flash chromatography on silica gel eluting withhexane-ethyl acetate (4:1) resulted in a white foam (0.47 g). Treatmentof the white foam with diethyl ether and sonication resulted in a whitesolid (0.37g), m.p. 169.5-171° C.

[0423]¹H NMR (400MHz, DMSO-d₈): δ5.32 (br, 4H), 5.93 (m, 1H), 5.97 (s,1H), 6.83 (m, 1H), 7.01 (d, 1H), 7.18 (m, 2H), 7.32 (t, 2H), 7.41, (d,1H), 6.45-7.60 (m, 5H), 7.93 (d, 1H), 7.97 (d, 1H). MS [EI, m/z]:414[M]⁺.

[0424] Anal. Calcd. for C₂₉H₂₂ N₂O+0.4 H₂O: C, 82.60, H, 5.45, N, 6.64.Found: C, 82.71, H, 5.44, N, 6.54.

EXAMPLE 24 [2-Chloro-4-(naphthalen-1-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

[0425] Step A. (4-Bromo-2-chloro-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]

[0426] N,N-Dimethylformamide (1 drop) was added to a solution of4-bromo-2-chiorobenzoic acid (2.20 g, 9.35 mmol) in anhydroustetrahydrofuran (20 mL). Oxalyl chloride (1.46 g, 11.46 mmol) was addedand the mixture was warmed to reflux. The resultant solution was cooledto ambient temperature before being evaporated to dryness to give thecrude acid chloride as a gold viscous liquid, which was used withoutfurther purification. To a mixture of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.44 g, 7.79 mmol) and triethylamine (0.95g, 9.35 mmol) in dichloromethane (40 mL) cooled in an ice bath, wasadded dropwise a solution of the acid chloride in dichloromethane (20mL). The cooling bath was removed and after stirring for 22 hours, thereaction mixture was washed sequentially with water, saturated aqueoussodium bicarbonate, 0.5 N hydrochloric acid and water. Thedichloromethane solution was dried over anhydrous sodium sulfate,filtered, then evaporated to dryness to yield an off-white foam.Purification by flash chromatography on silica gel eluting withhexane-ethyl acetate (2:1) resulted in a white foam (3.02 g), m.p.77-80° C. This material was used as is in the next step.

[0427]¹H NMR (400MHz, DMSO-d6): δ5.45 (br, 4H), 7.02 (t, 1H), 7.07 (td,1H), 7.14 (td, 1H), 7.32 (br, 1H), 7.38 (d, 2H), 7.68 (br , 1H). MS [EI,m/z]: 400[M]⁺.

[0428] Anal. Calcd. for C₁₉H₁₄BrCIO: C, 56.81, H, 3.51, N, 6.97. Found:C, 56.30, H, 3.32, N, 6.75.

[0429] Step B.[2-Chloro-4-(naphthalen-1-yl)-phenyl]-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone

[0430] 1-Naphthaleneboronic acid (0.52 g, 3.00 mmol) was added to amixture (4-bromo-2-chloro-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step A (1.27 g, 3.15 mmol) and sodiumcarbonate (0.53 g, 4.98 mmol) in toluene (22.5 mL), ethanol (4.5 mL) andwater (9 mL). The resultant solution was purged with nitrogen for 10minutes, then tetrakis(triphenylphosphine)palladium (0.18 g, 0.06 mmol)was added. The reaction mixture was heated to reflux for 76 hours. Thesolution was cooled to ambient temperature, then filtered through a padof Celite, which was subsequently rinsed with ethyl acetate. Thecombined filtrate was diluted to 100 mL water/ethyl acetate (1:1). Theaqueous layerwas extractedwith ethyl acetate, and the combined organiclayer was dried over anhydrous magnesium sulfate, filtered, andevaporated to dryness to yield a brown oil. Purification by flashchromatography on silica gel eluting with hexane-ethyl acetate (5:1)resulted in a white solid which was dried under vacuum (0.62 g), m.p.115-117.5° C.

[0431]¹H NMR (400MHz, DMSO-d₆): δ5.91 (t, 1H), 6.02 (br, 1H), 6.84 (br,1H), 7.14 (m, 2H), 7.24 (d, 1H), 7.34, (d, 1H), 7.95 (d, 1H), 7.98 (d,1H). MS [(+)ESI, m/z]: 449[M+H]⁺.

[0432] Anal. Calcd. for C₂₉H₂₁CIN₂O+0.25 H₂O: C, 76.72, H, 4.79, N,6.17. Found C, 76.72, H 4.53, N, 5.95.

EXAMPLE 25 [4-(4-Methyl-naphthalen-1-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

[0433] Step A. 4-(4-Methyl)-napthalen-1-yl-benzoic acid

[0434] To a mixture of 1-bromo-4-methyl napthalene (1.11 g, 5.00 mmol)and 4-carboxyphenyl boronic acid (1.00 g, 6.00 mmol) in ethylene glycoldimethyl ether (20 mL) was added a solution of sodium carbonate (2.37 g,22.38 mmol) in water (18.75 mL). The resultant mixture was purged withnitrogen for 20 minutes before tetrakis (triphenylphosphine)palladium(0) (0.03 g, 0.02 mmol) was added. The reaction mixture washeated to reflux for 68 hours. After the solution cooled to ambienttemperature, the solvent was removed in vacuo and the residue wasacidified with 5 N hydrochloric acid to produce an orange-brown solidthat was isolated by vacuum filtration. This material was used withoutfurther purification in the next step.

[0435]¹H NMR (300MHz, DMSO-d₆): δ2.70 (s, 3H), 7.57 (d, 2H), 8.07 (d,2H).

[0436] Step B.[4-(4-Methyl-naphthalen-1-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

[0437] N,N-Dimethylformamide (2 drops) was added to a solution of4-(4-methyl) -napthalen-1-yl-benzoic acid of Step A (0.90 g, 3.43 mmol)in anhydrous tetrahydrofuran (10 mL). Oxalyl chloride (0.52 g, 4.12mmol) was added and the mixture was warmed to reflux. The resultantsolution was cooled to ambient temperature before being evaporated todryness to give the crude acid chloride as a brown residue, which wasused without further purification. To a mixture of10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine (0.53 g, 2.86 mmol)and triethylamine (0.35 g, 3.43 mmol) in dichloromethane (10 mL) cooledin an ice bath was added dropwise a solution of the crude acid chloridein dichloromethane (10 mL). The cooling bath was removed and afterstirring for 137 hours, the reaction mixture was washed sequentiallywith water, saturated aqueous sodium bicarbonate, and saturated aqueoussodium chloride. The dichloromethane solution was dried over anhydrousmagnesium sulfate, filtered, then evaporated to dryness to yield anamber oil. Purification by flash chromatography on silica gel elutingwith hexane-ethyl acetate (4:1) resulted in a tan foam (0.49 g).Treatment of this material with diethyl ether and sonication resulted inan off-white solid (0.37 g), m.p. 160-162° C.

[0438]¹H NMR (400MHz, DMSO-d6): 62.66 (s, 3H), 5.32 (br, 4H), 5.93 (t,1H), 5.97(br, 1H), 6.83 (t, 1H), 7.01 (d, 1H), 7.22 (d, 2H), 7.28 ( d,2H), 7.39 (t, 3H), 7.45 (m, 2H), 7.57 (m, 2H), 8.06 (d, 1H). MS [(+)ESI,m/z]: 429[M+H]⁺.

[0439] Anal. Calcd. for C₃₀H₂₄N₂O+0.13 H₂O: C, 83.63, H, 5.67, N, 6.50.Found: C, 83.63, H 5.64, N, 6.43.

EXAMPLE 26 Methyl10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1.4]benzodiazepine-8-carboxylate

[0440] Step A. [4-(2-Formyl-1H-pyrrole-1-yl)methyl]-3-nitro]-benzoicacid methyl ester

[0441] To a suspension of sodium hydride (8.1 g, 60% suspension in oil)in N,N -dimethylformamide (25 mL) was added dropwise over 15 minutes asolution of pyrrole 2-carboxaldehyde (9.1 g, 1 equiv.) inN,N-dimethylformamide (25 mL). After the addition, the reaction mixturewas stirred for 30 minutes and then cooled to 0° C. A solution of4-bromomethyl-2-nitrobenzoic acid (25.0 g, 1 equiv.) in N,N-dimethylformamide (50 mL) was added dropwise over 20 minutes. After theaddition, the reaction mixture was stirred at room temperature for 1hour and then iodomethane (1.2 eq.) was added. The reaction mixture wasstirred at room temperature overnight and diluted with water (200 mL).The solid was filtered, washed with water and dried over anhydrouspotassium carbonate in vacuo at 50° C. to provide the crude titlecompound as a brown solid (26 g).which was used as such in the nextstep.

[0442] Step B. 10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylic acid methyl ester

[0443] To a stirred solution of tin(II) chloride dihydrate (23 g, 3.5eq) in 2 N hydrochloric acid (106 mL) was added the[4-(2-formyl-1H-pyrrole-1-yl)methyl]-3-nitro]-benzoic acid methyl esterof Step A (8 g). Methanol (200 mL) was then added to this solution andthe reaction mixture was stirred at 40° C. for 2 hours. The reaction wasthen cooled to room temperature, quenched by the addition of saturatedaqueous sodium carbonate (20 mL) and filtered through Celite. The filterpad was washed with methanol and hot ethyl acetate. The filtrate andwashings were combined, concentrated in vacuo to a volume of 300 mL andextracted with ethyl acetate. The combined extracts were dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo to avolume of 200 mL. Acetic acid (1 g) and 10% palladium on charcoal (1.5g) were added and the mixture was hydrogenated overnight at atmosphericpressure. The reaction was then filtered through Celite and the solventremoved in vacuo to give a dark brown crystalline solid (16.4 g). Thiswas dissolved in dichloromethane and filtered through a silica padeluting with dichloromethane to provide the title compound as a yellowcrystalline solid (11.7 g). Recrystallization from 1,2-dichloroethaneyielded a yellow crystalline solid (5.7 g), m.p. 198-200° C.

[0444]¹H NMR(CDCl₃, 200 MHz): δ3.95 (s, 3H), 4.50 (s, 2H), 5.20 (s, 2H),6.05 (t, 2H), 6.70 (t, 1H), 7.05 (d, 1H), 7.15 (s, 1H), 7.20 (d, 1H),7.30 (s, 1H).

[0445] Step C. Methyl10-{[2-methyl-2′4rifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1.4]benzodiazepine-8-carboxylate

[0446] To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-5 carboxylic acid methyl ester of Step B(1.64 g) in 1,2-dichloroethane (25 mL) was added4-(2-trifluoromethylphenyl)-3-methylbenzoyl chloride (2.0 g, 1.1 eq)prepared in the manner of Example 1, Step D and triethylamine (1.0 g)and the mixture was stirred at room temperature overnight. The solventwas then removed in vacuo and the residue chromatographed on silica geleluting with 10% ethyl acetate in petroleum ether to provide the titlecompound as a white crystalline solid, m.p. 180-182° C.

[0447]¹H NMR (DMSO-d₆, 400 MHz): δ1.80 (s, 3H), 3.70 (s, 3H), 5.0-5.5(br, 4H), 5.80 (t, 1H), 6.00 (s, 1H), 6.85 (t, 1H), 6.90 (s, 1H), 7.00(br, 1H), 7.20 (d, 1H), 7.35 (s, 1H), 7.60 (t, 2H), 7.70 (t, 2H), 7.75(d, 1H), 7.80 (d, 1H). MS [(+)ESI, m/z]: 505[M+H]⁺.

[0448] Anal. Calcd. for C₂₉H₂₃F₃N₂O₃: C, 69.04; H, 4.60; N, 5.55. Found:C, 67.76; H, 4.30; N, 5.40 .

EXAMPLE 27[4-(2,5-Dimethyl-1-H-pyrrol-1-yl)-3-methoxy-phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

[0449] A solution of (4-amino-3-methoxy-phenyl)[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone prepared in the manner ofAlbright et al., E.P.636625-A2 (0.675g, 2 mmol) and acetonyl acetone(0.3 mL, 2.5 mmol) in benzene (100 mL) was treated with a crystal ofpara-toluenesulfonic acid. The stirred solution was warmed to reflux for46 hrs using a Dean Stark trap. The reaction was cooled to roomtemperature, diluted with dichloromethane (100 mL), washed withsaturated aqueous sodium bicarbonate then water. The residue (oil, 0.900g) was flash chromatography on silica gel eluting with 20% ethyl acetatein hexane to yield 0.610 g of the title compound as a white foam.Recrystallization of a sample of this material yielded yellow crystals,m.p. 141-144° C.

[0450]¹H NMR (400MHz, DMSO-d₆): δ1.72 (s, 6H), 3.52 (s, 3H), 5.33 (br,4H), 5.69 (s, 3H), 5.93 (t, 1H), 5.97 (br, 1H), 6.82(t, 1H),. 6.96 (q,3H), 7.06 (t, 1H), 7.17 (t, 1H), 7.45 (d, 1H), MS [(+)ESI m/z]:412[M+H]⁺.

[0451] Anal. Calcd. for C₂₆H₂₅N₃O₂: C75.89, H, 6.12, N, 10.12. Found:C75.89, H, 5.95, N, 10.15.

EXAMPLE 28 [6-(Naphthalen-1-yl)-pyridin-3-yl]-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin -10-yl]methanone

[0452] Step A.(6-Chloro-pyridin-3-yl)-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

[0453] A solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine(100 mmol) and N,N-diisopropylethyl amine (130 mmol) in dichloromethane(500 mL) was cooled to 0° C. 6-Chloronicotinoyl chloride (130 mmol) wasadded dropwise under nitrogen. The solution was stirred for one hour asit returned to room temperature. The reaction mixture was filteredthrough a sica gel pad, washed with 0.5 N sodium hydroxide and water,dried over anhydrous magnesium sulfate. The solution was again filteredthrough a silica gel pad and evaporated to dryness in vacuo. Theresidual oil crystallized from diethyl ether to provide the titlecompound as a colorless crystalline solid, m.p. 165-167° C.

[0454]¹HNMR 9400 Mhz, DMSO-d₆): δ5.35 (br, 4H), 5.91 (t, 1H), 5.97 (s,1H), 6.83 (t, 1H), 7.0 (br d, 1H), 7.18 (t, 1H), 7.19 (t, 1H), 7.39 (d,1H), 7.46 (dd, 1H), 7.71 (d, 1H), 8.26 (s, 1H). MS [EI, m/z]: 323[M]⁺.

[0455] Anal. Calcd. for C₁₈H₁₄CIN₃O: C, 66.77, H, 4.36, N, 12.98. Found:C, 65.91, H, 4.18, N 12.69.

[0456] Step B.[6-(Naphthalen-1-yl)-pyridin-3-yl]-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

[0457] A suspension of(6-chloro-pyridin-3-yl)-[10,11-dihydro-5H-pyrrolo{2,1-c][1,4]benzodiazepin-10-yl]methanoneof Step A (0.645 g, 1.9 mmol) and naphthalene boronic acid (0.372 g, 2.1mmol) in a mixture of toluene (1.2 mL), ethanol (2 mL) and 1M aqueoussodium carbonate (0.4 mL) was sparged with nitrogen for 10 minutes. Tothis was added palladium(I) acetate (0.026 g, 0.1 mmol). The mixture washeated at reflux under a static pressure of nitrogen for 48 hrs. Thereaction was diluted with ethyl acetate and water. The organic layer waswashed with saturated aqueous sodium bicarbonate then water. The samplewas dried over anhydrous magnesium sulfate, filtered and concentrated invacuo to a brown oil. Flash chromatography of the residue on silica geleluting with 20-50% ethyl acetate in hexane, yielded 0.180 g of a solidwhich was recrystallized from chloroform to provide the title compoundas off white crystals, m.p. 155-158° C.

[0458]¹H NMR (400MHz, DMSO-d₆): δ5.40 (br, 4H), 5.93(m, 1H), 5.99(s,lH), 6.84 (s, 1H), 7.08(br d, 1H), 7.16 (t, 1H), 7.23 (t, 1H), 7.52(m, 6H), 7.84(d, 2H), 7.98 (dd, 2H), 8.55 (s, 1H). MS [(+)ESI, m/z]:416[M+H]⁺.

[0459] Anal. Calcd. for C₂₈H₂₁N₃O+0.5 H₂O: C, 79.22, H, 5.23, N, 9.90.,Found: C, 79.08, H, 4.94, N, 9.73.

EXAMPLE 29 (6-Phenyl-pyridin-3-yl)-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

[0460] The title compound was prepared in the manner of Example 28 usingphenylboronic acid (0.269 g),(6-chloro-pyridin-3-yl-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanoneof Example 28, Step A (0.645 g) and palladium(I) acetate (0.01 7g), in amixture of toluene (1 2 mL), 1 M aqueous sodium carbonate (4 mL) andethanol (2 mL). The initially obtained foam (0.387 g) was purified byHPLC (Primesphere C18, 5×25 cm column eluting with 55% acetonitrile inwater containing 0.1% formic acid) to yield the title product (0.200 g)as a yellow solid. Recrystallization of a sample from acetone/hexaneyielded yellow needles, m.p. 171-174° C.

[0461]¹H NMR (400MHz, DMSO-dr): δ5.37 (br, 4H), 5.92 (t, 1H), 5.97 (s,1H), 6.83 (t, 1H), 7.03 (d, 1H), 7.10 (t, 1H), 7.18 (t, 1H), 7.46 (m,4H), 7.73(d, 1H), 7.85 (d, 1H), 8.03 (dd, 2H), 8.44 (s, 1H). MS [(+)ESI,m/z]: 366[M+H]⁺.

[0462] Anal. Calcd. for C₂₄H₁₉N₃O+0.25 H₂O: C, 77.92, H, 5.31, N, 11.36.Found: C, 77.70, H, 5.23, N, 11.39.

EXAMPLE 30[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3,5-dimethyl-phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

[0463] Step A. Methyl4-(2,5-dimethyl-1H-pyrrol-1-yl)-3,5-dimethylbenzoate

[0464] Methyl 4-amino-3,5-dimethylbenzoate [prepared in the manner ofChang et al., WO Patent 9631492 A1](1.24g, 6.9 mmol), was converted intothe title compound (1.55 g) in the manner of Example 27.Recrystallization from aqueous methanol yielded a white solid, m.p.104-106° C.

[0465]¹H NMR (300 MHz, CDCl₃): δ1.95 (s, 6H), 2.00 (s, 6H), 3.95 (s,3H), 5.95 (br, 2H), 7.85 (s, 2H).

[0466] Step B. 4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3,5-dimethylbenzoic acid

[0467] Methyl 4-(2,5-dimethyl-1H-pyrrol-1-yl)-3,5-dimethylbenzoate ofStep A (1.55g, 6 mmol) was dissolved in ethanol (100 mL) and treatedwith 1 M sodium hydroxide (9 mL). The solution was refluxed overnight,cooled to room temperature, acidified with 1 N hydrochloric acid, anddiluted into water and ethyl acetate. The organic layer was washed withwater until neutral, dried with anhydrous sodium sulfate, filtered andevaporated in vacuo to yield the title compound as a a cream coloredsolid (1.36 g).

[0468]¹H NMR (300 MHz, CDCl₃): δ1.87 (s, 6H), 2.00 (s, 6H), 5.95 (s,2H), 7.90 (s, 2H).

[0469] Step C. [4-(2,5-Dimethyl-iH-pyrrol-1-yl)-3,5-dimethyl-phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

[0470] A solution of 4-(2,5-dimethyl-1H-pyrrol-1-yl)-3,5-dimethylbenzoicacid of Step B (0.495 g, 2 mmol) was dissolved in tetrahydrofuran (10mL) and treated with N,N -dimethylformamide (10 μL) followed by oxalylchloride (250 μL, 2.85 mmol) added dropwise to control gas evolution.When the gas evolution subsided, the solution was warmed to reflux for 5minutes. The solution was then concentrated in vacuo, the residue wasdissolved in tetrahydrofuran and evaporated to dryness. The residue wasredissolved in dichloromethane and the solution added dropwise to a coldsolution (0° C.) of 10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine(0.372mg, 2 mmol) and Hunig's base (0.5 mL) in dichloromethane. Thesolution was stirred overnight at room temperature, washed successivelywith 1 N hydrochloric acid, saturated aqueous bicarbonate, and brine.The sample was then dried over anhydrous sodium sulfate, filtered andevaporated in vacuo to a yellow foam (0.75 g). Flash chromatography ofthis material on silica gel eluting with a solvent gradient of 10 to 20%of ethyl acetate in hexane, provided a white solid (0.130 g).Recrystallization of this material from ethyl acetate/hexane providedthe title compound (0.120 g) as flat crystals, m.p. 197-199° C.

[0471]¹H NMR (400 MHz, CDCl₃): δ1.75 (s, 3H), 1.77 (s, 3H), 5.18 (br,4H), 5.89 (s, 2H), 6.05 (br, 1H), 6.08 (t, 1H), 6.69 (t, 1H), 6.85 (br,1H), 7.03 (br, 3H), 7.16 (t, 1H), 7.35 (d, 1H). MS [(+)APCI, m/z]:410[M+H]⁺.

[0472] Anal. Calcd. for C₂₇H₂₇N₃O+0.25 H₂O: C, 78.33, H, 6.69, N, 10.15.Found: C, 78.04, H 6.53, N, 10.08.

EXAMPLE 31[3-Methyl-4-(4-pyridinyl)phenyl]-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

[0473] Step A. (4-Bromo-3-methylphenyl)[10,11-dihydro-5H-pyrrolo[2,1c][1,4]benzodiazepin-10-yl]methanone

[0474] A solution of 4-bromo-3-methyl benzoic acid (4.3 g, 2 mmol) indry tetrahydrofuran (100 mL) was cooled to 0° C. under nitrogen. To thiswas added N,N -dimethylformamide (50 μL) followed by oxalyl chloride(2.2 mL, 25mmol) dropwise to control the gas evolution. When the gasevolution ceased, the mixture was warmed to reflux for 5 minutes thencooled to room temperature and concentrated in vacuo. The sample wastreated with tetrahydrofuran and evaporated to dryness (twice) to yieldthe crude acid chloride as an orange oil. A solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (3.60g, 20 mmol) andHunig's base (4.35 mL, 25 mmol) in dichloromethane was cooled to 0° C.,and a solution of the crude acid chloride in dichloromethane (25 mL) wasadded dropwise. The mixture was stirred overnight at room temperature,washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonateand brine. The solution was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to yield a solid (8.01 g) which waspurified by flash chromatography on silica gel eluting with 20% ethylacetate in hexane to provide the title compound (6.03 g) as a whitesolid.

[0475]¹H NMR (300 MHz, CDCl₃): δ2.30 (s, 3H), 5.20 (br, 4H), 6.05 (d,2H), 6.70 (s, 1H), 6.85 (br, 2H), 7.17 (m, 2H), 7.30 (m, 2H), 7.37 (d,1H).

[0476] Step B.[3-Methyl-4-(pyridin-4-yl)phenyl]-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

[0477] A suspension of (4-bromo-3-methylphenyl)[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone of Step A (1.14g, 2.9 mmol),pyridine-4-boronic acid (0.368 mg, 2.9 mmol) and sodium carbonate (0.760g, 7.2 mmol) in a mixture of toluene (30 mL), water (10 mL), and ethanol(5 mL) was sparged with nitrogen for 15 minutes. To this was addedtetrakis(triphenylphosphine)palladium(O) (0.027 g) and the mixture washeated to reflux under a static pressure of nitrogen. After 24 hoursadditional boronic acid (0.128 mg, 1 mmol) and sodium carbonate (0.116g) were added and the heating was continued for 24 hours. Additionalcatalyst (0.012 g) was added and heating was continued for another 24hours. The mixture was partitioned between ethyl acetate and hexane. Thewater layer was washed twice with ethyl acetate and the combined organiclayers were dried over anhydrous magnesium sulfate and stripped to asolid. Flash chromatography of the residue on silica gel eluting with30% ethyl acetate in hexane provided a solid which was recrystallizedfrom ethyl acetate/hexane to provide the title compound (0.254 g) as tanplates m.p. 208-210° C.

[0478]¹H NMR (400 MHz, DMSO-d₆): δ1.75 (s, 3H), 1.77 (s, 3H), 5.18 (br,4H), 5.89 (s, 2H), 6.05 (br, 1H), 6.08 (t, 1H), 6.69 (t, 1H), 6.85 (br,1H), 7.03 (br, 3H), 7.16 (t, 1H), 7.35 (d, 1H). MS [EI, m/z]:379[M]^(+.)

[0479] Anal. Calcd. for C₂₅H₂₁N₃O+0.5 H₂O: C, 77.30, H, 5.71, N, 10.82.Found: C, 77.01, H 5.37, N, 10.68.

EXAMPLE 3210-{[3,6-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine

[0480] Step A.2,5-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylic acid

[0481] A suspension of 4-bromo-2,5-dimethoxybenzoic acid [prepared inthe manner of Bortnik et al., Zh. Org. Khim. 8, 340 (1972)](2.43g, 9mmol), 2-trifluoromethylphenyl boronic acid (5.3 g, 28 mmol), andpotassium carbonate (6.21g, 60 mmol) in dioxane (40 mL) was sparged withnitrogen and treated with tetrakis(triphenylphosphine)palladium(0)(0.328 g, 0.2 mmol). The mixture was heated to reflux for 48 hours,cooled, acidified with 1 N hydrochloric acid and extracted with ethylacetate. The extracts were dried over anhydrous magnesium sulfate,filtered and stripped to a solid which was used as such in the nextstep.

[0482]¹H NMR (300 MHz,CDCl₃): δ3.90 (s, 3H), 4.05 (s, 3H), 7.30 (d, 1H),7.70 (s, 1H).

[0483] Step B.10[3,6-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

[0484] The title compound was prepared in the manner of Example 31, StepA using 2,5-dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylicacid of Step A (1.63 g, 5 mmol), oxalyl chloride (700 liL, 8 mmol),N,N-dimethylformamide (10PL), 10,11-dihydro -5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.93 g, 5 mmol) and Hucnig's base (1.78 ml,10 mmol). Flash chromatography over silica gel using a solvent gradientfrom 30% ethyl acetate in hexane to 100% ethyl acetate provided thetitle compound (0.900 g) as a solid. Recrystallization fromacetonelhexane yielded white needles, m.p. 210-213° C.

[0485]¹ H NMR (400 MHz, DMSO-d₆: 6 3.41 (s, 3H), 3.56 (s, 3H), 5.21 (br,4H), 5.90 (t, 1H), 5.96 (s, 1H), 6.50 (s, 1H), 6.80 (s, 1H), 7.00 (s,2H), 7.07 (s, 1H), 7.10 (t, 1H), 7.18 (d, 1H), 7.37 (d, 1H), 7.53 (t,1H), 7.62 (t, 1H), 7.73 (d, 1H). MS [(+)ESI, m/z]: 493[M+H]⁺.

[0486] Anal. Calcd. for C₂₈H₂₃ F₃N₂O₃: C, 68.29, H, 4.71, N, 5.69.Found: C, 67.98, H, 4.66, N, 5.61.

EXAMPLE 33{[10-(2-Methoxy)-2′-chloro-[1,1′-biphenyl]-4-yl]carbonyl}-[(2S)-[(2-pyrrolidin-1-yl)methyl]pyrrolidin-1-yl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl-methanone

[0487]10-{[2-methoxy-2′-chloro[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid (0.230 g, 0.54mmol) [prepared from trifluoromethanesulfonic acid4-formyl-2-methoxy-phenyl ester of Example 19, Step A and 2-chlorophenylboronic acid, in the manner of Example 19, Steps B-E],1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.120 g,0.625 mmol) and 1-hydroxybenzotriazole (0.087 g, 0.625 mmol) were addedto a flask containing N,N -dimethylformamide (15 mL). To the homogeneoussolution was added (S)-(+)-1-[(2-pyrrolidin-1-yl)methyl]-pyrrolidine(0.100 g, 0.625 mmol) and stirring continued at room temperatureovernight. At the end of this time the solution was poured into waterand extracted with ethyl acetate. The combined extracts were washed withwater, dried and concentrated and the residue was chromatographed onsilica gel, eluting with 95:5 chloroform:methanol. The pure fractionswere concentrated, and the residue azeotroped and triturated severaltimes with hexane to yield the title product, m.p. 109° C.

[0488]¹H NMR (400 MHz, DMSO-d6): δ1.4-1.98 (m, 8H), 3.57 (m, 2H), 4.35(br, 1H), 5.46 (br, 1H), 5.62 ( br, 1H), 6.06 (s, 1H), 6.40 (s, 1H),6.84-7.49 (m 7H). MS [(+)APCI, m/z]: 609[M+H]⁺.

EXAMPLE 3410-[(6-Chloro-3-methoxy-2′-ethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methylpiperidin-4-yl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0489] Step A.10-{[6-Chloro-3-methoxy-2′-ethoxy[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid

[0490] Prepared by treatment of10-{[6-chloro-3-methoxy-2′-ethoxy-1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Example 17 with trichloroacetyl chloride,followed by basic hydrolysis of the intermediate trichloroacetate esterin the manner of Example 15, Step D.

[0491] Step B.10-[(6-Chloro-3-methoxy-2′-ethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methylpiperidin-4-yl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamidePrepared by coupling the10-{[6-chloro-3-methoxy-2′-ethoxy[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step A with1-methyl-4-(methylamino)piperidine (1.25 equiv.) in the manner ofExample 16.

EXAMPLE 35N-[3-(Dimethylamino)propyl]-N-methyl-10-[(6-chloro-3-methoxy-2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0492] Prepared by coupling of the[(6-chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 18, with3-(dimethylaminopropyl)-1-methyl amine (1.25 equiv.), in the manner ofExample 11.

EXAMPLE 36[4-(3-Dimethylaminopropyl)-piperazin-1-yl]-{10-[4-(naphthalen-1-yl)-phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepin-3-yl-methanone

[0493] Step A. 10-[4-(Naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid

[0494] Prepared by treatment of[4-(naphthalen-1-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1c][1,4]benzodiazepin-10-yi]-methanone of Example 23 withtrichloroacetyl chloride, followed by basic hydrolysis of theintermediate trichloroacetate ester in the manner of Example 15, Step D.

[0495] Step B.[4-(3-Dimethylaminopropyl)-piperazin-1-yl]-{10-[4-(naphthalen-1-yl)-phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl-methanone

[0496] The title compound was prepared by coupling the10-[4-(naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step A, with1-(3-dimethylamino-propyl)-piperazine (1.25 equiv) in the manner ofExample 4.

EXAMPLE 37(4-Methyl-piperazin-1-yl)-{10-[2-chloro-[4-(naphthalen-1-yl)]phenyli]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl-methanone

[0497] Step A.10-{[2-Chloro-4-(naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid

[0498] Prepared by treatment of[2-chloro-4-(naphthalen-1-yl)-phenyl]-(10,11-dihydro -5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone of Example 24 withtrichloroacetyl chloride, followed by basic hydrolysis of theintermediate trichloroacetate ester in the manner of Example 15, Step D.

[0499] Step B.(4-Methyl-piperazin-1-yl)-{10-[2-chloro-[4-(naphthalen-1-yl)]phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl-methanone

[0500] The title compound was prepared by the coupling the10-[2-chloro-4-(naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step A, with1-methyl-piperazine (1.25 equiv) in the manner of Example 2.

EXAMPLE 38 10-{[2-Methyl-2′-trifluoromethyl-[I,1′-biphenyl]-4-yl]carbonyl}-8-(piperidine-1-carbonyl)-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylicacid-methyl-(1-methyl -piperidin-4-yl)-amide hydrochloride salt

[0501] Step A.10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-8-carboxylic acid sodium salt

[0502] To a stirred solution of methyl10-{[2-methyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1.4]benzodiazepine-8-carboxylate of Example 26 (0.200 g) inethanol (5 mL) was added 2.5 N sodium hydroxide (4 mL). The reactionmixture was then stirred overnight at room temperature and the solventremoved in vacuo. The residue was acidified with 2 N hydrochloric acidand extracted with diethyl ether. The combined extracts were dried overanhydrous magnesium sulfate and filtered, and the the filtrateevaporated to dryness. The residue was dissolved in anhydrous ethanoland treated with 2.5 N sodium hydroxide (1.0 equiv.). After stirring for30 minutes at room temperature, the solvent was removed in vacuo toprovide the title compound sodium salt as a white solid, m.p. 210° C.

[0503]¹H NMR (DMSO-d₆, 400 MHz): 5 1.85 (s, 3H), 5.20 (br, 3H), 5.90 (s,2H), 6,80 (t, 1H), 6.90-7.80 (m, 11H). MS [(+)APCI, m/z]: 491[M+H]⁺.

[0504] Anal. Calcd. for C₂₈H₂₁F₃N₂O₃Na +H₂O: C, 63.27; H, 4.36; N, 5.27.Found: C, 63.04; H, 4.21; N, 4.99.

[0505] Step B.8-[(Piperidin-1-yl)carbonyl]-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

[0506] Prepared by coupling of10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylic acid of Step A with piperidine,in the manner of Example 2.

[0507] Step C.10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-8-(piperidine-1-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid-methyl-(1-methyl-piperidin-4-yl)-amide hydrochloride salt

[0508] Prepared by treatment of8-[(piperidin-1-yl)carbonyl]-{[2-methyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step B with diphosgene (1.1 equiv.) andtriethylamine (1.5 equiv.) followed by1-methyl-4-(methylamino)piperidine (1.5 equiv.) in the manner of Example13.

EXAMPLE 39[3-Methyl-4-(pyridin-4-yl)-phenyl]-{[(2S)-3-[(2-pyrrolidin-1-yl)methyl]pyrrolidin-1-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl-methanone

[0509] Step A.10-[3-Methyl-4-(4-pyridinyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1c][1,4]benzodiazepine-3-carboxylic acid

[0510] To a stirred solution of[3-methyl-4-(pyridin-4-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone of Example 31, Step B(5 mmol) and N,N-diisopropylethyl amine (12 mmol) in dichloromethane(200 mL) cooled to 0° C. was added dropwise a solution oftrichloroacetyl chloride (12 mmol) in dichloromethane. The temperaturewas maintained at 0° C. until the addition was complete. The reactionwas stirred overnight as it warmed to room temperature. The solution wasthen washed with 10% aqueous sodium bicarbonate and the organic layerwas dried, concentrated and filtered through a pad of silica gel with1:1 ethyl acetate/hexane containing 0.1% acetic acid. The filtrate wasconcentrated in vacuo and the residue was dissolved in acetone and 1 Nsodium hydroxide (2:1,v/v) and stirred at room temperature for 1 hourand then the pH was adjusted to pH, 4 with glacial acetic acid. Thesolution was concentrated to one half the volume in vacuo and theresidue extracted with ethyl acetate. The combined organic layers weredried and evaporated to an oil which was triturated with hexane to yielda solid (0.98 g).

[0511] Step B.[3-Methyl-4-(pyridin-4-yl)-phenyl]-{[(2S)-3-[(2-pyrrolidin-1-yl)methyl]pyrrolidin-1-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl-methanone

[0512] The title compound was obtained from the carboxylic acid of StepA and (S)-(+) -1-[(2-pyrrolidinyl)methyl]-pyrrolidine ((1.2 equiv.), inthe manner of Example 20.

EXAMPLE 4010-[(6-Phenyl-pyridin-3-yl)carbonyl]-N-methyl-N-(1-methyl-piperidin-4-yl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0513] Step A.10-(Methoxycarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid

[0514] A solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine(5 mmol) and N,N-diisopropylethyl amine (12 mmol) in dichloromethane(100 mL) was cooled to 0° C. and treated dropwise withtrichloroacetylchloride (12 mmol) in dichloromethane (20 mL). Thesolution was maintained at 0° C. for two hours and then allowed to warmto room temperature overnight. The solution was then treated withmethanol (25 mL) and stirring was continued for 2 hours. The solutionwas washed with 0.1 N hydrochloric acid, water and brine, dried overanhydrous magnesium sulfate, filtered and concentrated to yield thetitle compound as a white solid, m.p. 153-154° C. (dec.).

[0515] Anal. Calcd. for C₁₅H₁₄N₂O₄+0.06 C₄H₈O₂+0.07 C₃H₆O: C, 62.77, H,5.08, N, 9.48. Found: C, 62.26, H, 5.22, N, 9.37.

[0516] Step B.10-(Methoxycarbonyl)-[N-methyl-N-(1-methyl-piperidin-4-yl)]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0517] The title compound was prepared by coupling the10-(methoxycarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of step A with1-methyl-4-(methylamino)piperidine (1.2 equiv.), in the manner ofExample 38.

[0518] Step C.N-Methyl-N-(1-methyl-piperidin-4-yl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0519] A solution of10-(methoxycarbonyl)-[N-methyl-N-(1-methyl-piperidin-4-yl)]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide(5 mmol) of Step B in methanol (50 mL) was treated with potassiumcarbonate and stirred at room temperature overnight. Water was thenadded to the solution and the pH adjusted to 6 with 6N hydrochloricacid. The solution was extracted with ethyl acetate, and the combinedorganic layers were dried over anhydrous magnesium sulfate, andevaporated to dryness The residual oil was triturated with ethyl acetateand hexane to yield the title compound as a powder.

[0520] Step D.10-[(6-Phenyl-pyridin-3-yl)carbonyl]-N-methyl-N-(1-methyl-piperidin-4-yl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0521] A solution of 6-phenyl-nicotinyl chloride (6 mmol) (prepared bythe method of Ogawa et al., WO 9534540) in dichloromethane (2OmL) wasadded dropwise to a cold (0° C.) solution ofN-Methyl-N-(1-methyl-piperidin-4-yl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamideof Step C (5 mmol) and N,N-diisopropylethyl amine (6 mmol) indichloromethane (100 mL). The solution was stirred at 0° C. for 2 hoursand then allowed to warm to room temperature overnight. The solution waswashed with pH, 6 buffer, and brine, dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was chromatographed onsilica gel using 5% methanol in chloroform containing 0.5% ammoniumhydroxide, to provide the title compound.

EXAMPLE 41[4-(3-Dimethylaminopropyl)-piperazin-1-yl]-[10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepin-3-yl]-methanone

[0522] Prepared by treatment of10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Example 9, with 1-[(3-dimethylamino)propyl]-piperazine (1.2equiv.) in the manner of Example 4.

EXAMPLE 42N-[2-(Dimethylamino)ethyl]-10-{[6-chloro-3-methoxy-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3carboxamide

[0523] Prepared by treatment of10-{[6-chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Example 15 with 3-(dimethylamino)ethy-1-methylamine (1.2equiv.), in the manner of Example 22.

EXAMPLE 4310-[(2′-Chloro-6-chloro-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methylpiperidin-4-yl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0524] To a stirred solution of10-{[2′-chloro-6-chloro-3-methoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 16, Step C(0.250 g, 0.49 mmol) was added 1-methyl-4-(methylamino)piperidine (0.076g, 0.59 mmol) followed by 1-hydroxybenzotriazole (0.073 g, 0.54 mmol),1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.093 g,0.54 mmol), and N,N-diisopropylethyl amine (0.096 g, 0.74 mmol). Afterstirring overnight, the reaction mixture was diluted with chloroform,washed with saturated aqueous sodium bicarbonate and brine, dried overanhydrous magnesium sulfate, filtered and evaporated to dryness. Theresidue was flash chromatographed over silica gel eluting with 5%methanol in chloroform containing 0.5% ammonium hydroxide, to providethe title compound as white powder (0.100 g), 92.95% pure by analyticalHPLC [Primesphere C-18 column (2.0×150 mm); mobile phase: gradient from10 to 90% acetonitrile/water containing 0.1% phosphoric acid, 2 to 20minute gradient].

[0525]¹H NMR (DMSO-d₆, 400 MHz) 6 1.22 (s, 1H), 1.77 (br, 2H), 1.97 (br,2H ), 2.89 (s, 3H), 3.44 (br, 3H), 5.29 (s, 2H), 6.08 (d, 1H), 6.26 (d,1H), 6.68 (s, 1H), 6.97-7.61 (m, 1OH). MS [(+)ESI, m/z]: 617[M+H]⁺.

[0526] Anal. Calcd. for C₃₄H₃₄C₁₂N₄O₃+0.25 C₄H₈O₂: C, 65.73, H, 5.67, N,8.76. Found: C 65.95, H, 5.82, N, 8.49.

EXAMPLE 44{3-[4-(3-Dimethylamino-propyl)-piperazin-1-yl]carbonyl}-[4-(4-methyl-naphthalen-1-yl)phenyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl-methanone

[0527] Step A.10-{[4-(4-Methyl-naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid

[0528] Prepared from[4-(4-methyl-naphthalen-1-yl)-phenyl]-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl]methanone of Example 25 bytreatment with trichloroacetyl chloride, followed by basic hydrolysis ofthe intermediate trichloroacetate ester in the manner of Example 1,Steps E and F.

[0529] Step B.{3-[4-(3-Dimethylamino-propyl)-piperazin-1-yl]carbonyl}-[4-(4-methyl-naphthalen-1-yl)phenyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl-methanone

[0530] Prepared by the coupling of10-{[4-(4-methyl-naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step A, with 1-[3-(dimethylamino)propyl]-piperazine (1.2 equiv.)in the manner of Example 4.

EXAMPLE 4510-{[6-(Naphthalen-1-yl)-pyridin-3-yl]carbonyl}-N-methyl-N-(1-methyl-piperidin-4-yl)-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxamide

[0531] Step A.10-{[6-(Naphthalen-1-yl)-pyridin-3-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[1,2-c][1.4]benzodiazepine-3-carboxylicacid

[0532] Prepared from[6-(naphthalen-1-yl)-pyridin-3-yl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanoneof Example 28 by treatment with trichloroacetyl chloride, followed bybasic hydrolysis of the intermediate trichloroacetate ester in themanner of Example 40, Step A.

[0533] Step B.10-{[6-(Naphthalen-1-yl)-pyridin-3-yl]carbonyl}-N-methyl-N-(1-methyl-piperidin-4-yl)-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxamide

[0534] Prepared by the coupling of10-{[6-(naphthalen-1-yl)-pyridin-3-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[1,2-c][1.4]benzodiazepine-3-carboxylicacid of Step A, and 1-methyl -4-(methylamino)-piperidine (1.25 equiv) inthe manner of Example 40, Step B.

EXAMPLE 46{[10-(3,6-Dimethoxy)-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-[(2S)-[(2-pyrrolidin-1-yl)methyl]-pyrrolidin-1-yl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl-methanone

[0535] Step A.10-{[3,6-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]-carbonyl}-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxylicacid

[0536] Prepared from10-{[3,6-dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]-carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Example 32 and trichloroacetyl chloride,followed by basic hydrolysis of the intermediate trichloroacetate ester,in the manner of Example 1, Steps E and F.

[0537] Step B.{[10-(3,6-Dimethoxy)-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-[(2S)-[(2-pyrrolidin-1-yl)methyl]-pyrrolidin-1-yl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl-methanone

[0538] Prepared from10-[(3,6-dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]-carbonyl}-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxylicacid of Step A and (S)-(+)-1-[(2-pyrrolidin-1-yl)methyl]-pyrrolidine (1equiv.) in the manner of Example 33.

[0539] The following examples were prepared according to the GeneralProcedures A-K described below.

[0540] General Procedure A

[0541] Step A. An appropriately substituted haloaryl carboxylic acid(1.1 mol) was converted to the acid chloride by using oxalyl chloride(1.5 mmol) and a catalytic amount of N,N-dimethylformamide indichloromethane. Upon consumption of the acid as determined by HPLCanalysis, all volatiles were removed in vacuo. The resulting residue wasdissolved in dichloromethane and added dropwise to a stirred and cooled(0° C.) solution of an appropriately substituted10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine (1 mmol) andN,N-diisopropylethyl amine (1.2 mmol) in dichloromethane. After 1-16hours, the mixture was diluted with dichloromethane and washed with 10%aqueous sodium bicarbonate. The combined organic extracts were driedover anhydrous sodium sulfate, filtered and concentrated.

[0542] Step B. To the residue was added an appropriately substitutedboronic acid (1.2 mmol), potassium carbonate (2.5 mmol),tetrabutylammonium bromide (1 mmol), palladium(II) acetate (3% mole) andwater/acetonitrile (1:1.2 mL). The mixture was heated to 70° C. for 1.5hours, then ethyl acetate was added and the organic phase washed withwater. The solution was filtered through a small plug of Celite andconcentrated to dryness.

[0543] Step C. The residue was dissolved in dichloromethane andN,N-diisopropylethyl amine (2 mmol) was added. The flask was purged withnitrogen and trichloroacetyl chloride was added dropwise to the stirredreaction mixture. After 16 hours, the reaction was quenched by addingaqueous potassium carbonate (100g/300 mL) and the organic phase removed.The aqueous layer was extracted with additional dichloromethane and thecombined extracts dried over anhydrous sodium sulfate, filtered andconcentrated .

[0544] Step D. The crude product from Step C was dissolved intetrahydrofuran (1 mL) and 2N sodium hydroxide (1.5 mL) was added. Themixture was heated (70° C.) for 1.5 hours, 2N hydrochloric acid wasadded and the product extracted with ethyl acetate. The organic phasewas dried, filtered and concentrated. The residue was purified by columnchromatography using a gradient of ethyl acetate in hexane contaning 1%glacial acetic acid as the eluant.

[0545] Step E. To a stirred solution of a carboxylic acid of Step Dabove (1.85 mmol) in anhydrous tetrahydrofuran (14 mL) was added1,1′-carbonyl diimidazole in one portion. The mixture was stirred atroom temperature (6-8 hours). The progress of the reaction was monitoredby HPLC and when the starting carboxylic acid was consumed, the mixturewas worked up to provide the intermediate imidazolide.

[0546] Step F. An aliquot of a tetrahydrofuran solution (400 μL, 0.05mmole) containing the imidazolide of Step E (0.05 mmol) was treated witha 0.25 M solution of an appropriate amine (0.1 mmol). The mixture washeated at 60° C. and the progress of the reaction followed by HPLC. Thesolvent was removed and the residue dissolved in dichloromethane (1 mL).The organic phase was washed with brine-water (1:1, v/v, 1 mL) and theaqueous layer extracted with additional dichloromethane. The combinedextracts were dried and evaporated to dryness and the residue purifiedby flash chromatography on silica gel. The column (prepacked in 2.5%methanol in dichloromethane contaning 1% triethylamine) was eluted witha solvent gradient from 2.5 to 5% methanol in dichloromethane, toprovide desired title compound. The desired title compounds were eitherobtained as crystalline solids by exposure to diethyl ether or werefurther converted into their salts by any of the following procedures.

[0547] Step G. Compounds prepared according to Step E that dissolved indiethyl ether were treated with a stoichiometric amount of 1 Nhydrochloric acid in diethyl ether whereby the hydrochloride saltsprecipitated out as white solids. Compounds that did not conform to theabove category, were dissolved in the minimal amount of tetrahydrofuran,then diluted with diethyl ether. The hydrochloride salts were formedupon addition of 1 N hydrochloric acid in diethyl ether with stirring.Compounds that did not immediately precipitate out of solution werestirred for 12-16 hours whereupon a white solid precipitated out.

[0548] General Procedure B

[0549] To a stirred solution of an appropriately substituted carboxylicacid of General Procedure A, Step D (2 mmol),1-ethyl-3-(3-dimethylamino-propyl) carbodiimide (0.229 g, 2.2 mmol) anda catalytic amount of 4-(dimethylamino)pyridine in dichloromethane (6mL) was added the appropriately substituted amine (2.2 mmol) indichloromethane (2 mL). The reaction was allowed to stir at roomtemperature for 16 hours, then diluted with dichloromethane. The organiclayer was washed with water, saturated aqueous sodium bicarbonate, driedover anhydrous sodium sulfate and evaporated to dryness. The residue waspurified by flash chromatography on silica gel (prepacked indichloromethane containing 2.5% methanol and 1% triethylamine and elutedwith a solvent gradient of 2.5 to 5% methanol in dichloromethane) toprovide the desired title compound.

[0550] General Procedure C

[0551] Triphosgene (742 mg, 2.5 mmol) was added to a stirred solution ofa carboxylic acid of General Procedure A, Step D (5.0 mmol) indichloromethane (10 mL). The clear solution was allowed to stir at roomtemperature (14 hours) after which time the solution turned red. To thereaction mixture was added a solution of the required amine (10.0 mmol)and N,N-diisopropylethyl amine (10.0 mmol) in dichloromethane (5 mL).The mixture was diluted with dichloromethane and washed with water andbrine. The organic phase was dried, filtered and concentrated to afforda residue which was purified by flash chromatography on silica gel. Thecolumn (prepacked in 2.5% methanol in dichloromethane contaning 1%triethylamine) was eluted with a solvent gradient from 2.5 to 5%methanol in dichloromethane, to provide the title compound.

[0552] General Procedure D

[0553] A stirred solution of a carboxylic acid of General Procedure A,Step D (3.54 mmol) and the appropriately substituted amine (3.72 mmol)in N,N-dimethylformamide (10 mL) was cooled to 0° C.N,N-diisopropylethyl amine (3.89 mmol) was added and the mixture stirredfor five minutes. O-(1-Benzotriazolyl)-N, N, N′, N′-tetramethyluroniumhexafluorophosphate (HBTU) (1.42 g, 3.72 mmol) was added to the mixturein one portion. HPLC analysis revealed that the reaction was completewithin five minutes. The solvent was removed at reduced pressure. Theresidue was diluted with water and extracted with ethyl acetate. Thecombined extracts were dried and concentrated to dryness. The residuewas purified by flash chromatography on silica gel (prepacked in ethylacetate containing 2% triethylamine and eluted with 100% ethyl acetate)to provide the title compound.

[0554] General Procedure E

[0555] To a 0.25 M solution of a carboxylic acid of General Procedure A,Step D (200 μL) in N,N-dimethylformamide was added sequentially a 0.5 Msolution of N,N -diisopropylethyl amine (200 μL) inN,N-dimethylformamide, and a 0.25 M solution of0-(7-aza-1-benzotriazolyl)-N, N, N′, N′-tetramethyluroniumhexafluorophosphate (HATU) (210 μL) in N,N-dimethylformamide. Themixture was stirred vigorously at room temperature and then a 0.25 Msolution of the appropriately substituted amine (200 JL) inN,N-dimethylformamide was added. Stirring was continued for 24 hours atroom temperature, then the mixture was diluted with ethyl acetate, andwashed with 1:1 water! brine. The organic layer was dried andconcentrated to dryness. The residue was purified by flashchromatography on silica gel (prepacked in ethyl acetate containing 2%triethylamine and eluted with 100% ethyl acetate) to provide the titlecompound.

[0556] General Procedure F

[0557] Step A. To a solution of an appropriately substituted anilinocarboxylic acid in methanol was added thionyl chloride. The mixture washeated for 16 hours. The volatiles were removed under reduced pressureand the hydrochloride salt of the carboxylic acid methyl ester wasrecovered after trituration with methanol/diethyl ether. The solid wasdissolved in concentrated hydrochloric acid and cooled. An aqueoussolution of sodium nitrite was added and the mixture was stirred at 0°C. for one hour. An aqueous solution of KI/I₂ was prepared and added tothe cooled mixture so that the reaction temperature did not exceed 0° C.After 1-2 hours the reaction was complete as evidenced by TLC/HPLCanalysis. The product was recovered by extraction with ethyl acetate.The combined extracts were dried, filtered and concentrated to affordthe desired substituted aryl iodide which could be further purified byrecrystallization.

[0558] Step B. To a solution of an appropriately substituted aryl halidemethyl ester of Step A (2 mmol) and an appropriately substituted boronicacid (2 mmol) in 20% aqueous acetone was added cesium carbonate (3 mmol)followed by palladium(II) acetate (60 μmol). The mixture was heated (70°C.) with stirring for 8-16 hours. The reaction was concentrated toremove the acetone after TLCIHPLC analysis indicated the reaction wascomplete. The aqueous phase was extracted with ethyl acetate and thecombined extracts were filtered through a pad of Celite. The filtratewas washed with 5% aqueous sodium bicarbonate and brine, dried overanhydrous sodium sulfate, filtered and evaporated to dryness. Theresidue was purified by flash chromatography on silica gel .

[0559] Step C. The product from Step B was dissolved in tetrahydrofuran(1 mL) and 2N sodium hydroxide (1.5 mL) was added. The mixture washeated (70° C.) for 1.5 hours, 2N hydrochloric acid was added and theproduct extracted with ethyl acetate. The organic phase was dried,filtered and concentrated. The residue was purified by columnchromatography using ethyl acetate in hexane contaning 1% glacial aceticacid as the eluant.

[0560] Step D. To a suspension of the carboxylic acid of Step C (60μmol) in dichloromethane (100 μL) was added a 0.45 M solution of oxalylchloride (200 μL) in dichloromethane followed by dichloromethane (100pL) containing a catalytic amount of N,N-dimethylformamide. The mixturewas allowed to sit at room temperature for 16 hours, then the volatileswere removed in vacuo to afford the crude acid chloride. A solution ofthe acid chloride in tetrahydrofuran (0.3 M, 200 μL), was utilized toacylate a solution (0.3 M, 200 lIL) of an appropriately substituted10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine in tetrahydrofuranaccording to the General Procedure A, Step A.

[0561] General Procedure G

[0562] A mixture of an appropriately substituted aryl bromide methylester (or an aryl iodide methyl ester of General Procedure F, Step A)(8.3 mmol), an appropriately substituted boronic acid (9.1 mmol),potassium carbonate (20.8 mmol), tetrabutylammonium bromide (or iodide)(8.3 mmol), palladium(II) acetate and water (8-9 mL) was stirred withheating (70° C.) for 1.5 hours, whereupon the reaction was deemedcomplete by HPLC analysis. The oily upper layer was extracted with ethylacetate, the extracts washed with brine , dried and concentrated todryness. The residue was filtered through a column of silica gel toprovide the desired coupled product of General Procedure F, Step B.

[0563] General Procedure H

[0564] The coupling of an appropriately substituted aryl bromide methylester (or an aryl iodide methyl ester of General Procedure F, Step A)(8.3 mmol) to an appropriately substituted pyridyl borane was carriedout using potassium hydroxide as the base, in the presence oftetrabutylammonium bromide (or iodide) and a tetrakis(triphenylphoshine)palladium (0) catalyst essentially according to the published procedureof M. Ishikura, Synthesis, 936-938 (1994), to provide the desiredcoupled product of General Procedure F, Step B.

[0565] General Procedure I

[0566] The coupling of an appropriately substituted aryl bromide methylester (or an iodide methyl ester of General Procedure F, Step A) (8.3mmol) to an appropriately substituted boronic acid was carried outessentially according to General Procedure F, Step B except that thesolvent was acetonitrile.

[0567] General Procedure J

[0568] The desired substituted aryl iodide of General Procedure F, StepA was prepared by reaction of an appropriately substituted aminocarboxylic acid in concentrated hydrochloric acid at 0° C. with anaqueous solution of sodium nitrite followed by the addition of anaqueous solution of KI/l₂ at 0° C., followed by esterification of theresulting iodo aryl carboxylic acid with methanolic hydrochloric acid.

[0569] General Procedure K

[0570] The acylation of an activated appropriately substitutedarylpyridine carboxylic acid of Procedure H was carried out bydissolving the acid (0.06 mmol) in a solution of oxalyl chloride indichloromethane (12 mg/200 μL) followed by a catalytic amount of N,N-dimethylformamide in dichloromethane (100 tL). After stirring at roomtemperature for 16 hours, the volatiles were removed and tetrahydrofuranadded, followed by the addition of a solution of the appropriatelysubstituted 10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine andN,N-diisopropylethyl amine (1:2 molar ratio) in tetrahydrofuran. Afterstirring for 20 hours, the reaction was worked up essentially asdescribed in General Procedure A, Step A.

EXAMPLE 47{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone

[0571] HRMS [(+)ESI, m/z]: 569.23190[M+H]⁺. Calcd. for C₃₃H₃₄CIN₄O₃:569.23140

EXAMPLE 48{10-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone

[0572] HRMS [(+)ESI, m/z]: 521.25443[M+H]⁺. Calcd. for C₃₂H₃₃N₄O₃:521.25472.

EXAMPLE 49{10-[(2′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone

[0573] HRMS [(+)ESI, m/z]: 535.26907[M+H]⁺. Calcd. for C₃₃H₃₅N₄O₃:535.27037

EXAMPLE 50{10-[(2,2′-Dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone

[0574] HRMS [(+)ESI, m/z]: 519.27490[M+H]⁺. Calcd. for C₃₃H₃₅N₄O₂:519.27546.

EXAMPLE 51{10-[(3′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone

[0575] HRMS [(+)ESI, m/z]: 535.26968[M+H]⁺. Calcd. for C₃₃H₃₅N₄O₃:535.27037

EXAMPLE 52{10-[(2′-Methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone

[0576] HRMS [(+)ESI, m/z]: 505.25870[M+H]⁺. Calcd. for C₃₂H₃₃N₄O₂:505.25981

EXAMPLE 53{10-[(2-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone

[0577] HRMS [(+)ESI, m/z]: 535.26942[M+H]⁺. Calcd for C₃₃H₃₅N₄O₃:535.27037

EXAMPLE 54{10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone

[0578] HRMS [(+)ESI, m/z]: 585.22598[M+H]⁺. Calcd. for C₃₃H₃₄CIN₄O₄:585.22631.

EXAMPLE 55 {10-[3-Methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone

[0579] HRMS [(+)ESI, m/z]: 571.26974[M+H]⁺. Calcd. for C₃₆H₃₅N₄O₃:571.27037.

EXAMPLE 56{10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone

[0580] HRMS [(+)ESI, m/z]: 551.26482[M+H]⁺. Calcd. for C₃₃H₃₅N₄O₄:551.26529

EXAMPLE 57{10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone

[0581] HRMS [(+)ESI, m/z]: 551.26514[M+H]⁺. Calcd. for C₃₃H₃₅N₄O₄:551.26529

EXAMPLE 58{10-[2-Chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone

[0582] HRMS [(+)ESI, m/z]: 575.22071[M+H]⁺. Calcd. for C₃₅H₃₂CIN₄O₂:575.22083

EXAMPLE 59(4-Methyl-1,4-diazepan-1-yl)(10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)methanone

[0583] HRMS [(+)ESI, m/z]: 587.26266[M+H]⁺. Calcd. for C₃₄H₃₄F₃N₄O₂:587.26284

EXAMPLE 60{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone

[0584] HRMS [(+)ESI, m/z]: 583.24744[M+H]⁺. Calcd. for C₃₄H₃₆CIN₄O₃:583.24705

EXAMPLE 61{10-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone

[0585] HRMS [(+)ESI, m/z]: 535.26998[M+H]⁺. Calcd. for C₃₃HmN₄O₃:535.27037

EXAMPLE 62{10-[(2′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone

[0586] HRMS [(+)ESI, m/z]: 549.28533[M+H]⁺. Calcd. for C₃₄H₃₇N₄O₃:549.28602

EXAMPLE 63{10-[(2,2′-Dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone

[0587] HRMS [(+)ESI, m/z]: 533.29054[M+H]⁺. Calcd. for C₃₄H₃₇N₄O₂:533.29111

EXAMPLE 64{10-[(3′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone

[0588] HRMS [(+)ESI, m/z]: 549.28413[M+H]⁺. Calcd. for C₃₄H₃₇N₄O₃:549.28602

EXAMPLE 65{10-[(2′-Methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone

[0589] HRMS [(+)ESI, m/z]: 519.27474[M+H]⁺. Calcd. for C₃₃Hs₅N₄02:519.27546

EXAMPLE 66{10-[(2-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone

[0590] HRMS [(+)ESI, m/z]: 549.28529[M+H]⁺. Calcd. for C₃₄H₃₇N₄O₃:549.28602

EXAMPLE 67{10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone

[0591] HRMS [(+)ESI, m/z]: 599.24153[M+H]⁺. Calcd. for C₃H₃₆CIN₄O₄:599.24196

EXAMPLE 68{10-[3-Methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone

[0592] HRMS [ESI(+), m/z]: 585.28342[M+H]⁺. Calcd. for C₃₇H₃₇N₄O₃:585.28602

EXAMPLE 69{10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone

[0593] HRMS [(+)ESI, m/z]: 565.28058[M+H]⁺. Calcd. for C₃₇H₃₇N₄O₃:565.28094

EXAMPLE 70 {10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone

[0594] HRMS [(+)ESI, m/z]: 565.28111[M+H]⁺. Calcd. for C₃₄H₃₇N₄O₄:565.28094

EXAMPLE 71{10-[2-Chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone

[0595] HRMS [(+)ESI, m/z]: 589.23633[M+H]⁺. Calcd. for C₃₆H₃₄CIN₄O₂:589.23648

EXAMPLE 72N-[3-(Dimethylamino)propyl]-10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0596] HRMS [(+)ESI, m/z]: 537.28687[M+H]⁺. Calcd. for C₃₃H₃₇N₄O₃:537.28602

EXAMPLE 73N-[3-(Dimethylamino)propyl]-10-[(2,2′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0597] HRMS [(+)ESI, m/z]: 521.29049[M+H]⁺. Calcd. for C₃₃H₃₇N₄O₂:521.29111

EXAMPLE 74N-[3-(Dimethylamino)propyl]-10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0598] HRMS [ESI(+), m/z]: 537.28588[M+H]⁺. Calcd. for C₃₃H₃₇N₄O₃:537.28602

EXAMPLE 75N-[3-(Dimethylamino)propyl]-10-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0599] HRMS [(+)ESI, m/z]: 523.26977[M+H]⁺. Calcd. for C₃₂H₃₅N₄O₃:523.27037

EXAMPLE 76N-[3-(Dimethylamino)propyl]-10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0600] HRMS [(+)ESI, m/z]: 507.27437[M+H]⁺. Calcd. for C₃₂H₃₅N₄O₂:507.27546

EXAMPLE 77N-[3-(Dimethylamino)propyl]-10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0601] HRMS [(+)ESI, m/z]: 537.28577[M+H]⁺. Calcd. for C₃₃H₇N₄O₃:537.28602

EXAMPLE 7810-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(dimethylamino)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0602] HRMS [(+)ESI, m/z]: 571.24731[M+H]⁺. Calcd. for C₃₃H₃₆CIN₄O₃:571.24705

EXAMPLE 7910-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(dimethylamino)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0603] HRMS [(+)ESI, m/z]: 587.24161[M+H]⁺. Calcd. for C₃₃H₃₆CIN₄O₄:587.24196

EXAMPLE 80N-[3-(Dimethylamino)propyl]-10-[3-methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0604] HRMS [(+)ESI, m/z]: 573.28422[M+H]⁺. Calcd. for C₃₆H₃₇N₄O₃:573.28602

EXAMPLE 8110-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(dimethylamino)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0605] HRMS [(+)ESI, m/z]: 553.27855[M+H]⁺. Calcd. for C₃₃H₃₇N₄O₄:553.28094

EXAMPLE 8210-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(dimethylamino)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0606] HRMS [(+)ESI, m/z]: 553.28083[M+H]⁺. Calcd. for C₃₃H₃₇N₄O₄:553.28094

EXAMPLE 8310-[2-Chloro-4-(1-naphthyl)benzoyl]-N-[3-(dimethylamino)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0607] HRMS [(+)ESI, m/z]: 577.23637[M+H]⁺. Calcd. for C₃₅H₃₄CIN₄O₂:577.23648

EXAMPLE 84N-[3-(Dimethylamino)propyl]-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1.4]benzodiazepine-3-carboxamide

[0608] HRMS [(+),ESI m/z]: 575.26427[M+H]⁺. Calcd. for C₃₃H₃₃F₃N₄O₂:575.26284

EXAMPLE 85N-[2-(Dimethylamino)ethyl]-N-methyl-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0609] HRMS [(+)ESI, m/z]: 575.26180[M+H]⁺. Calcd. for C₃₃H₃₄F₃N₄O₂:575.26284

EXAMPLE 8610-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(dimethylamino)ethyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0610] HRMS [(+)ESi, m/z]: 571.24735[M+H]⁺. Calcd. for C₃₃H₃₆CIN₄O₃:571.24705

EXAMPLE 8710-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(dimethylamino)ethyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0611] HRMS [(+)ESI, m/z]: 587.24165[M+H]⁺. Calcd. for C₃₅H₃₆CIN₄O₄:587.24196

EXAMPLE 88N-[2-(Dimethylamino)ethyl]-10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0612] HRMS [(+)ESI, m/z]: 537.28481[M+H]⁺. Calcd. for C₃₃H₃₇N₄O₃:537.28602

EXAMPLE 89N-[2-(Dimethylamino)ethyl]-10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-Nmethyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0613] HRMS [(+)ESI, m/z]: 537.28523[M+H]⁺. Calcd. for C₃₃H₃₇N₄O₃:537.28602

EXAMPLE 90N-[2-(Dimethylamino)ethyl]-10-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0614] HRMS [(+)ESI, m/z]: 523.26992[M+H]⁺. Calcd. for C₃₂H₃₅N₄O₃:523.27037

EXAMPLE 91N-[2-(Dimethylamino)ethyl]-N-methyl-10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0615] HRMS [(+)ESI, m/z]: 507.27458[M+H]⁺. Calcd. for C₃₂H₃₅N₄O₂:507.27546

EXAMPLE 92N-[2-(Dimethylamino)ethyl]-10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0616] HRMS [(+)ESI, m/z]: 537.28550[M+H]⁺. Calcd. for C₃₃H₃₇N₄O₃:537.28602

EXAMPLE 93N-[2-(Dimethylamino)ethyl]-10-[3-methoxy-4-(1-naphthyl)benzoyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0617] HRMS [(+)ESI, m/z]: 573.28467[M+H]⁺. Calcd. for C₃₆H₃₇N₄O₃:573.28602

EXAMPLE 9410-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(dimethylamino)ethyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0618] HRMS [(+)ESI, m/z]: 553.28019[M+H]⁺. Calcd. for C₃ ₃H₃₇N₄O₄:553.28094

EXAMPLE 9510-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(dimethylamino)ethyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0619] HRMS [(+)ESI, m/z]: 553.28093[M+H]⁺. Calcd. for C₃₃H₃₇N₄O₄:553.28094

EXAMPLE 9610-[2-Chloro-4-(1-naphthyl)benzoyl]-N-[2-(dimethylamino)ethyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0620] HRMS [(+)ESI, m/z]: 577.23624[M+H]⁺. Calcd. for C₃₅H₃₄CIN₄O₂:577.23648

EXAMPLE 97N-[3-(Dimethylamino)propyl]-N-methyl-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0621] HRMS [(+)ESI, m/z]: 589.27641[M+H]⁺. Calcd. for CuH₃₆F₃N₄O₂:589.27849

EXAMPLE 9810-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(dimethylamino)propyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0622] HRMS [(+)ESI, m/z]: 585.26286[M+H]⁺. Calcd. for C₃₄H₃₈CIN₄O₃:585.26270

EXAMPLE 9910-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(dimethylamino)propyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0623] HRMS [ESI(+), m/z]: 601.25755[M+H]⁺. Calcd. for C₃₄H₃8CIN₄O₄:601.25761

EXAMPLE 100N-[3-(Dimethylamino)propyl]-10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0624] HRMS [(+)ESI, m/z]: 551.30068[M+H]⁺. Calcd. for C₃₄H₃₉N₄O₃:551.30167

EXAMPLE 101N-[3-(Dimethylamino)propyl]-10-[(2,2′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0625] HRMS [(+)ESI, m/z]: 535.30614[M+H]⁺. Calcd. for C₃₄H₃₉N₄O₂:535.30676

EXAMPLE 102N-[3-(Dimethylamino)propyl]-10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0626] HRMS [(+)ESI, m/z]: 551.30006[M+H]⁺. Calcd. for C₃₄H₃₉N₄O₃:551.30167

EXAMPLE 103N-[3-(Dimethylamino)propyl]-10-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0627] HRMS [(+)ESI, m/z]: 537.28544[M+H]⁺. Calcd. for C₃₃H₃₇N₄O₃:537.28602

EXAMPLE 104N-[3-(Dimethylamino)propyl]-N-methyl-10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0628] HRMS [(+)ESI m/z]: 521.28955[M+H]⁺. Calcd. for C₃₃H₃₇N₄O₂:521.29111

EXAMPLE 105N-[3-(Dimethylamino)propyl]-10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0629] HRMS [(+)ESI, m/z]: 551.30117[M+H]⁺. Calcd. for C₃₄H₃₉N₄O₃:551.30167

EXAMPLE 106N-[3-(Dimethylamino)propyl]-10-[3-methoxy-4-(1-naphthyl)benzoyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0630] HRMS [(+)ESI, m/z]: 587.30108[M+H]⁺. Calcd. for C₃₇H₃9N₄O₃:587.30167

EXAMPLE 10710-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(dimethylamino)propyl]-N-methyl-10,1-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0631] HRMS [(+)ESI, m/z]: 567.29434[M+H]⁺. Calcd. for C₃₄H₃9N₄O₄:567.29659

EXAMPLE 10810-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(dimethylamino)propyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0632] HRMS [(+)ESI, m/z]: 567.29641[M+H]⁺. Calcd. for C₃₄H₃₉N₄O₄:567.29659

EXAMPLE 10910-[2-Chloro-4-(1-naphthyl)benzoyl]-N-[3-(dimethylamino)propyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0633] HRMS [(+)ESI, m/z]: 591.25210[M+H]⁺. Calcd. for C₃₆H₃₆CIN₄O₂:591.25213

EXAMPLE 110{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone

[0634] HRMS [(+)ESI, m/z]: 637.29447[M+H]⁺. Calcd. for C₃₈H₄₂CIN₄O₃:637.29400

EXAMPLE 111{10-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone

[0635] HRMS [(+)ESI, m/z]: 589.31729[M+H]⁺. Calcd. for C₃₇H₄₁N₄O₃:589.31732

EXAMPLE 112{10-[(2-Methyl-2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone

[0636] HRMS [(+)ESI, m/z]: 603.33228[M+H]⁺. Calcd. for C₃₈H₄₃N₄O₃:603.33297

EXAMPLE 113{10-[(2-Methyl-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone

[0637] HRMS [(+)ESI, m/z]: 587.33759[M+H]⁺. Calcd. for C H₄₃N₄O₂:587.33806

EXAMPLE 114{10-[(2-Methyl-3′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone

[0638] HRMS [(+)ESI, m/z]: 603.33180[M+H]⁺. Calcd. for C₃₈H₄₃N₄O₃:603.33297

EXAMPLE 115{10-[(2′-Methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone

[0639] HRMS [(+)ESI, m/z]: 573.32176[M+H]⁺. Calcd. for C₃₇H₄,N₄O₂:573.32241

EXAMPLE 116{10-[(2-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone

[0640] HRMS [(+)ESI, m/z]: 603.33259[M+H]⁺. Calcd. for C₃₈H₄₃N₄O₃:603.33297

EXAMPLE 117{10-[(6-Chloro-3-methoxy-3′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone

[0641] HRMS [(+)ESI, m/z]: 653.28981[M+H]⁺. Calcd. for C₃₈H₄₂CIN₄O₄:653.28891

EXAMPLE 118{10-[3-Methoxy-4-(1-naphthyl)-benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone

[0642] HRMS [(+)ESI, m/z]: 639.33115[M+H]⁺. Calcd. for C₄,H₄₃N₄O₃:639.33297

EXAMPLE 119{10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone

[0643] HRMS [(+)ESI, m/z]: 619.32688[M+H]⁺. Calcd. for C₃₈H₄₃N₄O₄:619.32789

EXAMPLE 120{10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone

[0644] HRMS [(+)ESI, m/z]: 619.32835[M+H]⁺. Calcd. for C₃₈H₄₃N₄O₄:619.32789

EXAMPLE 121{10-[(2-Chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone

[0645] HRMS [(+)ESI, m/z]: 643.28413[M+H]⁺. Calcd. for C₄oH₄₀CIN₄O₂:643.28343

EXAMPLE 122 {10-[(2-Methyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone

[0646] HRMS [(+)ESI, m/z]: 641.30863[M+H]⁺. Calcd. for C₃₈H₄oF₃N₄O₂:641.30979

EXAMPLE 123N-[3-(1H-Imidazol-1-yl)propyl]-10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0647] HRMS [(+)ES[, m/z]: 560.26553[M+H]⁺. Calcd. for C₃₄H₃₄N₅O₃:560.26562

EXAMPLE 12410-[(2,2′-Dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(1H-imidazol-1-yl)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0648] HRMS [(+)ESI, m/z]: 544.26958[M+Hl+. Calcd. for C₃₄H₃₄N₅O₂:544.27071

EXAMPLE 125N-[3-(1H-Imidazol-1-yl)propyl]-10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0649] HRMS [(+)ESI, m/z]: 560.26510[M+H]⁺. Calcd. for C₃₄H₃₄N₅O₃:560.26562

EXAMPLE 126N-[3-(1H-Imidazol-1-yl)propyl]-10-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0650] HRMS [(+)ESI, m/z]: 546.24888[M+H]⁺. Calcd. for C₃₃H₃₂N50₃:546.24997

EXAMPLE 127N-[3-(1H-Imidazol-1-yl)propyl]-10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0651] HRMS [(+)ESI, m/: 530.25497[M+H]⁺. Calcd. for C₃₃H₃₂N₅O₂:530.25506

EXAMPLE 128N-[3-(1H-lmidazol-1-yl)propyl]-10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0652] HRMS [(+)ESI, m/z]: 560.26575[M+H]⁺. Calcd. for C₃H₃₄N₅O₃:560.26562

EXAMPLE 12910-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(1H-imidazol-1-yl)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0653] HRMS [(+)ESI, m/z]: 594.22579[M+H]⁺. Calcd. for C₃₄H₃₃CIN₅O₃:594.22665

EXAMPLE 13010-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(1H-imidazol-1-yl)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0654] HRMS [(+)ESI, m/z]: 610.22084[M+H]⁺. Calcd. for C₃₄H₃₂CIN₅O₄:610.22156

EXAMPLE 131N-[3-(1H-Imidazol-1-yl)propyl]-10-[3-methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0655] HRMS [(+)ESI, m/z]: 596.26527[ M+H]⁺. Calcd. for C₃₇H₃₄N₅O₃:596.26562

EXAMPLE 13210-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(1H-imidazol-1-yl)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0656] HRMS [(+)ESI, m/z]: 576.26044[M+H]⁺. Calcd. for C₃H₃₄N₅O₄:576.26054

EXAMPLE 13310-[(2,3′-Dimethoxy[1,1′-biphenyl]4-yl)carbonyl]-N-[3-(1H-imidazol-1-yl)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0657] HRMS [(+)ESI, m/z]: 576.26011[M+H]⁺. Calcd. for C₃₄H₃₄N50₄:576.26054

EXAMPLE 13410-[2-Chloro-4-(1-naphthyl)benzoyl]-N-[3-(1H-imidazol-1-yl)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0658] HRMS [(+)ESI, m/z]: 600.21491[M+H]⁺. Calcd. for C₃₆H₃₁CIN₅O₂:600.21608

EXAMPLE 135N-[3-(1H-Imidazol-1-yl)propyl]-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0659] HRMS [(+)ESI, m/z]: 598.24213[M+H]⁺. Calcd. for C₃₄H₃₁F₃N₅O₂:598.24244

EXAMPLE 136{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone

[0660] HRMS [(+)ESI, m/z]: 623.27800[M+H]⁺. Calcd. for C₃₇H₄₀CIN₄O₃:623.27835

EXAMPLE 137{10-[(2′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone

[0661] HRMS [(+)ESI, m/z]: 589.31713[M+H]⁺. Calcd. for C₃₇H₄₁N₄O₃:589.31732

EXAMPLE 138{10-[(2,2′-Dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone

[0662] HRMS [(+)ESI, m/z]: 573.32179[M+H]⁺. Calcd. for C₃₇H₄₁N₄O₂:573.32241

EXAMPLE 139{10-[(3′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone

[0663] HRMS [(+)ESI, m/z]: 589.31726[M+H]⁺. Calcd. for C₃₇H₄₁N₄O₃:589.31732

EXAMPLE 140{10-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone

[0664] HRMS [(+)ESI, m/z]: 575.30111[M+H]⁺. Calcd. for C₃₆H₃₉N₄O₃:575.30167

EXAMPLE 141{10-[(2′-Methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone

[0665] HRMS [(+)ESI, m/z]: 559.30724[M+H]⁺. Calcd. for C₃₆H₃₉N₄O₂:559.30676

EXAMPLE 142{10-[(2-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone

[0666] HRMS [(+)ESI, m/z]: 589.31781[M+H]⁺. Calcd. for C₃₇H₄₁N₄O₃:589.31732

EXAMPLE 143{10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone

[0667] HRMS [(+)ESI, m/z]: 639.27294[M+H]⁺. Calcd. for C₃₇H₄₀CIN₄O₄:639.27326

EXAMPLE 144{10-[3-Methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone

[0668] HRMS [(+)ESI, m/z]: 625.31794[M+H]⁺. Calcd. for C₄₀H₄₁N₄O₃:625.31732

EXAMPLE 145{10-[(2,2′-Dimethoxy[1,1′-biphenyl]4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-l-piperidinyl]methanone

[0669] HRMS [(+)ESI, m/z]: 605.31251[M+H]⁺. Calcd. for C₃ ₇H₄₁N₄O₄:605.31224

EXAMPLE 146{10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone

[0670] HRMS [(+)ESI, m/z: 605.31137[M+H]⁺. Calcd. for C₃₇H₄,N₄O₄:605.31224

EXAMPLE 147{10-[2-Chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone

[0671] HRMS [(+)ESI, m/z]: 629.26756[M+H]⁺. Calcd. for C₃₉H₃₈CIN₄O₂:629.26778

EXAMPLE 148{10-{[2-Methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)[4-(1-pyrrolidinyl)-1-piperidinyl]methanone

[0672] HRMS [(+)ESI, m/z]: 627.29365[M+H]⁺. Calcd. for C₃₇H₃₈F₃N₄O₂:627.29414

EXAMPLE 14910-[(2′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0673] HRMS [(+)ESI, m/z]: 563.30179[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₃:563.30167

EXAMPLE 15010-[(2,2′-Dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0674] HRMS [(+) ESI, m/z]: 547.30585[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₂:547.30676

EXAMPLE 15110-[(3′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0675] HRMS [(+)ESI, m/z]: 563.30189[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₃:563.30167

EXAMPLE 15210-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0676] HRMS [(+)ESI, m/z3: 549.28510[M+H]⁺. Calcd. for C₃₄H₃ ₇N₄O₃:549.28602

EXAMPLE 15310-[(2′-Methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0677] HRMS [(+)ESI, m/z]: 533.29111[M+H]⁺. Calcd. for C₃₄H₃₇N₄O₂:533.29111

EXAMPLE 15410-[(2-Methoxy-2′-methyl[1,1′-biphenyl]4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0678] HRMS [(+)ESI, m/z]: 563.30195[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₃:563.30167

EXAMPLE 15510-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0679] HRMS [(+)ESI, m/z]: 597.26203[M+H]⁺. Calccd. for C₃₅H₃₈CIN₄O₃:597.26270

EXAMPLE 15610-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0680] HRMS [(+)ESI, m/z]: 613.25706[M+H]⁺. Calcd. for C₃₅H₃₈CIN₄O₄:613.25761

EXAMPLE 15710-[3-Methoxy-4-(1-naphthyl)benzoyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0681] HRMS [(+)ESI, m/z]: 599.30190[M+H]⁺. Calcd. for C₃₈H₃₉N₄O₃:599.30167

EXAMPLE 15810-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0682] HRMS [(+)ESI, m/z]: 579.29668[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₄:579.29659

EXAMPLE 15910-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0683] HRMS [(+)ESI, m/z]: 579.29558[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₄:579.29659

EXAMPLE 16010-[2-Chloro-4-(1-naphthyl)benzoyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0684] HRMS [(+)ESI, m/z]: 603.25172[M+H]⁺. Calcd. for C₃₇H₃₆CIN₄O₂:603.25213

EXAMPLE 16110-{[2-Methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0685] HRMS [(+)ESI, m/z]: 601.27838[M+H]⁺. Calcd. for C₃₅H₃₆F₃N₄O₂:601.27849

EXAMPLE 16210-[(2′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0686] HRMS [(+)ESI, m/z]: 563.30191[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₃:563.30167

EXAMPLE 16310-[(2,2′-Dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0687] HRMS [(+)ESI, m/z]: 547.30573[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₂:547.30676

EXAMPLE 16410-[(3′-Methoxy-2-methyl[1′1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0688] HRMS [(+)ESI, m/z]: 563.30176[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₃:563.30167

EXAMPLE 16510-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0689] HRMS [(+)ESI, m/z]: 549.28483[M+H]⁺. Calcd. for C₃H₃₇N₄O₃:549.28602

EXAMPLE 166 10-[(2′-Methyl[1,l¹′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0690] HRMS [(+)ESI, m/z]: 533.29125[M+H]⁺. Calcd. for C₃₄H₃₇N₄O₂:533.29111

EXAMPLE 16710-[(2-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0691] HRMS [(+)ESI, m/z]: 563.30226[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₃:563.30167

EXAMPLE 16810-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0692] HRMS [(+)ESI, m/z]: 597.26179[M+H]⁺. Calcd. for C₃₅H₃₈CIN₄O₃:597.26270

EXAMPLE 16910-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0693] HRMS [(+)ESI, m/z]: 613.25723[M+H]⁺. Calcd. for C₃₅H₃₈CIN₄O₄:613.25761

EXAMPLE 17010-[3-Methoxy-4-(1-naphthyl)benzoyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0694] HRMS [(+)ESI, m/z]: 599.30196[M+H]⁺. Calcd. for C₃₈H₃₉N₄O₃:599.30167

EXAMPLE 17110-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0695] HRMS [(+)ESI, m/z]: 579.29682[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₄:579.29659

EXAMPLE 17210-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0696] HRMS [(+)ESI, m/z]: 579.29546[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₄:579.29659

EXAMPLE 17310-[2-Chloro-4-(1-naphthyl)benzoyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0697] HRMS [(+)ESI, m/z]: 603.25172[M+H]⁺. Calcd. for C₃₇H₃₆CIN₄O₂:603.25213

EXAMPLE 174N-[2-(1-Methyl-2-pyrrolidinyl)ethyl]-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0698] HRMS [(+)ESI, m/z]: 601.27811[M+H]⁺. Calcd. for C₃₅H₃₆F₃N₄O₂:601.27849

EXAMPLE 17510-[(2′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0699] HRMS [(+)ESI, m/z]: 563.30205[M+H]⁺-Calcd. for C₃₅H₃₉N₄O₃:563.30167

EXAMPLE 17610-[(3′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0700] HRMS [(+)ESI, m/z]: 563.30249[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₃:563.30167

EXAMPLE 17710-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0701] HRMS [(+)ESI, m/z]: 549.28510[M+H]⁺. Calcd. for C H₃₇N₄O₃:549.28602

EXAMPLE 178N-Methyl-10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-(1-methyl-4-piperidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0702] HRMS [(+)ESI, m/z]: 533.29178[M+H]⁺. Calcd. for C₃₄H₃₇N₄O₂:533.29111

EXAMPLE 17910-[(2-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4benzodiazepine-3-carboxamide

[0703] HRMS [(+)ESI, m/z]: 563.30250[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₃:563.30167

EXAMPLE 18010-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0704] HRMS [(+)ESI, m/z]: 597.26325[M+H]⁺. Calcd. for C₃₅H₃₈CIN₄O₃:597.26270

EXAMPLE 18110-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl4-piperidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0705] HRMS [(+)ESI, m/z]: 613.25636[M+H]⁺. Calcd. for C₃₅H₃₈CIN₄O₄:613.25761

EXAMPLE 18210-[3-Methoxy-4-(1-naphthyl)benzoyl]-N-methyl-N-(1-methyl-4-piperidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0706] HRMS [(+)ESI, m/z]: 599.30260[M+H]⁺. Calcd. for C₃₈H₃₉N₄O₃:599.30167

EXAMPLE 183 10-[(2,2′-Dimethoxy[1,¹′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0707] HRMS [(+)ESI, m/z]: 579.29711[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₄:579.29659

EXAMPLE 184N-Methyl-N-(1-methyl-4-piperidinyl)-10-{[2-methyl-2′-(trifluoromethyl)[1,l¹′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0708] HRMS [(+)ESI, m/z]: 601.27917[M+H]⁺. Calcd. for C₃₅H₃₆F₃N₄O₂:601.27849

EXAMPLE 18510-[(2′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-3-pyrrolidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0709] HRMS [(+)ESI, m/z]: 549.28649[M+H]⁺. Calcd. for C₃₄H₃₇N₄O₃:549.28602

EXAMPLE 18610-[(3′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-3-pyrrolidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0710] HRMS [(+)ESI, m/z]: 549.28621[M+H]⁺. Calcd. for C₃₄H₃₇N₄O₃:549.28602

EXAMPLE 18710-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-3-pyrrolidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0711] HRMS [(+)ESI, m/z]: 535.26930[M+H]⁺. Calcd. for C₃₃H₃₅N₄O₃:535.27037

EXAMPLE 188N-Methyl-10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-(1-methyl-3-pyrrolidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0712] HRMS [(+)ESI, m/z]: 519.27588[M+H]⁺. Calcd. for C₃₃H₃₅N₄O₂:519.27546

EXAMPLE 18910-[(2-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-3-pyrrolidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0713] HRMS [(+)ESI, m/z]: 549.28615[M+H+. Calcd. for C₃₄H₇N₄O₃:549.28602

EXAMPLE 19010-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-3-pyrrolidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0714] HRMS [(+)ESI, m/z]: 583.24598[M+H]⁺. Calcd. for C₃₄H₃₆CIN₄O₃:583.24705

EXAMPLE 19110-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-3-pyrrolidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0715] HRMS [(+)ESI, m/z]: 599.24156[M+H]⁺. Calcd. for C₃₄H₃₆CIN₄O₄:599.24196

EXAMPLE 19210-[3-Methoxy-4-(1-naphthyl)benzoyl]-N-methyl-N-(1-methyl-3-pyrrolidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0716] HRMS [(+)ESI, m/z]: 585.28612[M+H]⁺. Calcd. for C₃₇H₃₇N₄O₃:585.28602

EXAMPLE 19310-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-3-pyrrolidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0717] HRMS [(+)ESI, m/z]: 565.28108[M+H)+. Calcd. for C₃₄H₃₇N₄O₄:565.28094

EXAMPLE 194N-Methyl-N-(1-methyl-3-pyrrolidinyl)-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0718] HRMS [ESI(+), m/z]: 587.26289[M+H]⁺. Calcd. for C₃₄H₃₄F₃N₄O₂:587.26284

EXAMPLE 195 {4-[2-(Dimethylamino)ethyl]-1-piperazinyl}{10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0719] HRMS [(+)ESI, m/z]: 592.32843[M+H]⁺. Calcd. for C₃₆H₄₂N₅O₃:592.32822

EXAMPLE 196{4-[2-(Dimethylamino)ethyl]-1-piperazinyl}(10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)methanone

[0720] HRMS [(+)ESI, m/z]: 630.30472[M+H]⁺. Calcd. for C₃₆H₃₉F₃N₅O₂:630.30504

EXAMPLE 197{10-[(6-Chloro,-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(dimethylamino)ethyl]-1-piperazinyl}methanone

[0721] HRMS [(+)ESI, m/z]: 626.28869[M+H]⁺. Calcd. for C₃₆H₄₁CIN₅O₃:626.28925

EXAMPLE 198{4-[2-(Dimethylamino)ethyl]-1-piperazinyl}{10-[(2,2′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0722] HRMS [(+)ESI, m/z]: 576.33266[M+H]⁺. Calcd. for C₃₆H₄₂N₅O₂:576.33331

EXAMPLE 199 {4-[2-(Dimethylamino)ethyl]-1-piperazinyl}{10-[(3′-methoxy-2-methyl[1,1′-biphenyl)-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-ylmethanone

[0723] HRMS [(+)ESI, m/z]: 592.32832[M+H]⁺. Calcd. for C₃₆H₄₂NO₃:592.32822

EXAMPLE 200 {4-[2-(Dimethylamino)ethyl]-1-piperazinyl}{10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0724] HRMS [(+)ESI, m/z]: 562.31789[M+H]⁺. Calcd. for C₃₅H₄₀N₅O₂:562.31766

EXAMPLE 201 {4-[2-(Dimethylamino)ethyl]-1-piperazinyl}{10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0725] HRMS [(+)ESI, m/z]: 592.32869[M+H]⁺. Calcd. for C₃₆H₄₂N₅O₃:592.32822

EXAMPLE 202{10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(dimethylamino)ethyl]-1-piperazinyl}methanone

[0726] HRMS [(+)ESI, m/z]: 642.28388[M+H]⁺. Calcd. for C₃₆H₄₁CIN₅O₄:642.28416

EXAMPLE 203 {4-[2-(Dimethylamino)ethyl]-1-piperazinyl}{10-[3-methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0727] HRMS [(+)ESI, m/z]: 628.32892[M+H]⁺. Calcd. for C₃₉H₄₂N₅O₃:628.32822

EXAMPLE 204{10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(dimethylamino)ethyl]-1-piperazinyl}methanone

[0728] HRMS [(+)ESI, m/z]: 608.32361[M+H]⁺. Calcd. for C₃₆H₄₂N₅O₄:608.32314

EXAMPLE 205{10-[2-Chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(dimethylamino)ethyl]-1-piperazinyl}methanone

[0729] HRMS [(+)ESI, m/z]: 632.27795[M+H]⁺. Calcd. for C₃₈H₃₉CIN₅O₂:632.27868

EXAMPLE 206{10-[(2′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone

[0730] HRMS [(+)ESI, m/z]: 634.33902[M+H]⁺. Calcd. for C₃₈H₄₄N50₄:634.33879

EXAMPLE 207{10-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone

[0731] HRMS [(+)ESI, m/z]: 620.32261[M+H]⁺. Calcd. for C₃₇H₄₂N₅O₄:620.32314

EXAMPLE 208{10-[(3′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone

[0732] HRMS [(+)ESI, m/z]: 634.33860[M+Hl+. Calcd. for C₃₈H₄₄N₅O₄:634.33879

EXAMPLE 209{10-[(2′-Methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone

[0733] HRMS [(+)ESI, m/z]: 604.32832[M+H]⁺. Calcd. for C₃₇H₄₂N₅O₃:604.32822

EXAMPLE 210{10-[(2-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone

[0734] HRMS [(+)ESI, m/z]: 634.33915[M+H]⁺. Calcd. for C₃₈H₄₄N₅O₄:634.33879

EXAMPLE 211{10-[(2,3′-Dimethoxy[1,1′-biphenyl]4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone

[0735] HRMS [(+)ESI, m/z]: 650.33299[M+H]⁺. Calcd. for C₃₈H₄₄N₅O₅:650.33370

EXAMPLE 212{10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyi}methanone

[0736] HRMS [(+)ESI, m/z]: 684.29459[M+H]⁺. Calcd. for C₃₈H₄₃C[N₅O₅:684.29473

EXAMPLE 213{10-[3-Methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone

[0737] HRMS [(+)ESI, m/z]: 670.33934[M+H]⁺. Calcd. for C₄₁H₄₄N₅O₄:670.33879

EXAMPLE 214{10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl1-1-piperazinyl}methanone

[0738] HRMS [(+)ESI, m/z]: 650.33399[M+H]⁺. Calcd. for C₃₈H₄₄N₅O₅:650.33370

EXAMPLE 215{10-[2-Chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone

[0739] HRMS [(+)ESI, m/z]: 674.28820[M+H]⁺. Calcd. for C₄₀H₄₁CIN₅O₃:674.28925

EXAMPLE 216(10-{[2-Methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl){4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone

[0740] HRMS [(+)ESI, m/z]: 672.31528[M+H]⁺. Calcd. for C₃₈H₄₁F₃N₅O₃:672.31560

EXAMPLE 217{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone

[0741] HRMS [(+)ESI, m/z]: 668.29857[M+H]⁺. Calcd. for C₃₈H₄₃CIN₅O₄:668.29981

EXAMPLE 218{10-[(2,2′-Dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone

[0742] HRMS [(+)ESI, m/z]: 618.34297[M+H]⁺. Calcd. for C₃₈HAN₅O₃:618.34387

EXAMPLE 219 (4-Allyl-1-piperazinyl){10-[(6-chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0743] HRMS [(+)ESI, m/z]: 595.24716[M+H]⁺. Calcd. for C₃₅H₃₆CIN₄O₃:595.24705

EXAMPLE 220 (4-Allyl-1-piperazinyl){10-[(2,2′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0744] HRMS [(+)ESI, m/z]: 545.29099[M+H]⁺. Calcd. for C₃₅H₃₇N₄O₂:545.29111

EXAMPLE 221 (4-Allyl-1-piperazinyl){10-[(2′-methoxy[1,1′-biphenyl]4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0745] HRMS [(+)ESI, m/z]: 547.27057[M+H]⁺. Calcd. for C₃₄H₃₅N₄O₃:547.27037

EXAMPLE 222 (4-Allyl-1-piperazinyl){10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0746] HRMS [(+)ESI, m/z]: 561.28578[M+H]⁺. Calcd. for C₃₅H₃₇N₄O₃:561.28602

EXAMPLE 223 (4-Allyl-1-piperazinyl){10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0747] HRMS [(+)ESI, m/z]: 561.28603[M+H]⁺. Calcd. for C₃₅H₃₇N₄O₃:561.28602

EXAMPLE 224 (4-Allyl-1-piperazinyl){10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0748] HRMS [(+)ESI, m/z]: 531.27586[M+H]⁺. Calcd. for C₃₄H₃₅N₄O₂:531.27546

EXAMPLE 225 (4-Allyl-1-piperazinyl) {10-[(2-methoxy-2′-methyl[1,1¹′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0749] HRMS [(+)ESI, m/z]: 561.28574[M+H]⁺. Calcd. for C₃₅H₃₇N₄O₃:561.28602

EXAMPLE 226 (4-Allyl-1-piperazinyl){10-[(6-chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0750] HRMS [(+)ESI, m/z]: 611.24297[M+H]⁺. Calcd. for C₃₅H₃₆CIN₄O₄:611.24196

EXAMPLE 227 (4-Allyl-1-piperazinyl){10-[(2,2′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0751] HRMS [(+)ESI, m/z]: 577.28073[M+H]⁺. Calcd. for C₃₅H₃₇N₄O₄:577.28094

EXAMPLE 228 (4-Allyl-1-piperazinyl){10-[(2,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0752] HRMS [(+)ESI, m/z]: 577.28057[M+H]⁺. Calcd. for C₃₅H₃₇N₄O₄:577.28094

EXAMPLE 229 (4-Allyl-1-piperazinyl){10-[2-chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0753] HRMS [(+)ESI, m/z]: 601.23590[M+H]⁺. Calcd. for C₃₇H₃₄CIN₄O₂:601.23648

EXAMPLE 230(4-Allyl-1-piperazinyl)(10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)methanone

[0754] HRMS [(+)ESI, m/z]: 599.26246[M+H]⁺. Calcd. for C₃₅H₃₄F₃N₄O₂:599.26284

EXAMPLE 231 (4-Allyl-1-piperazinyl){10-[3-methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0755] HRMS [(+)ESI, m/z]: 597.28585[M+H]⁺. Calcd. for C₃₈H₃₇N₄O₃:597.28602

EXAMPLE 232 (4-Isopropyl-1-piperazinyl){10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0756] HRMS [(+)ESI, m/z]: 563.30161[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₃:563.30167

EXAMPLE 233{10-[(2,2′-Dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-isopropyl-1-piperazinyl)methanone

[0757] HRMS [(+)ESI, m/z]: 547.30657[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₂:547.30676

EXAMPLE 234 (4-Isopropyl-1-piperazinyl){10-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0758] HRMS [(+)ESI, m/z]: 549.28582[M+H]⁺. Calcd. for C₃H₃₇N₄O₃:549.28602

EXAMPLE 235 (4-Isopropyl-1-piperazinyl){10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0759] HRMS [(+)ESI, m/z]: 563.30191[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₃:563.30167

EXAMPLE 236 (4-Isopropyl-1-piperazinyl){10-[3-methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone HRMS [(+)ESI, m/z]:599.30222[M+H]⁺. Calcd. for C₃₈H₃₉N₄O₃: 599.30167 EXAMPLE 237(4-isopropyl-1-piperazinyl){10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0760] HRMS [(+)ESI, m/z]: 563.30167[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₃:563.30167

EXAMPLE 238{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-isopropyl-1-piperazinyl)methanone

[0761] HRMS [(+)ESI, m/z]: 597.26324[M+H]⁺. Calcd. for C₃₅H₃₈CIN₄O₃:597.26270

EXAMPLE 239{10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-isopropyl-1-piperazinyl)methanone

[0762] HRMS [(+)ESI, m/z]: 613.25831[M+H]⁺. Calcd. for C₃₅H₃₈CIN₄O₄:613.25761

EXAMPLE 240(4-Isopropyl-1-piperazinyl)(10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)methanone

[0763] HRMS [(+)ESI, m/z]: 601.27873[M+H]⁺. Calcd. for C₃₅H₃₆F₃N₄O₂:601.27849

EXAMPLE 241{10-[(2,2′-Dimethoxy[1,1-biphenyl]4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-isopropyl-1-piperazinyl)methanone

[0764] HRMS [(+)ESI, m/z]: 579.29699[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₄:579.29659

EXAMPLE 242{10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-isopropyl-1-piperazinyl)methanone

[0765] HRMS [(+)ESI, m/z]: 579.29628[M+H]⁺. Calcd. for C₃₅H₃₉N₄O₄:579.29659

EXAMPLE 243{10-[2-Chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-isopropyl-1-piperazinyl)methanone

[0766] HRMS [(+)ESI, m/z]: 603.25170[M+H]⁺. Calcd. for C₃₇H₃₆CIN₄O₂:603.25213

EXAMPLE 244{10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-isopropyl-1-piperazinyl)methanone

[0767] HRMS [(+)ESI, m/z]: 533.29134[M+H]⁺. Calcd. for C₃₄H₃₇N₄O₂:533.29111

EXAMPLE 245 {4-[3-(Dimethylamino)propyl]-1-piperazinyl}{10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0768] HRMS [(+)ESI, m/z]: 606.34402[M+H]⁺. Calcd. for C₃₇HAN₅O₃:606.34387

EXAMPLE 246 {4-[3-(Dimethylamino)propyl]-1-piperazinyl}{10-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0769] HRMS [(+)ESI, m/z]: 592.32795[M+H]⁺. Calcd. for C₃₆H₄₂N₅O₃:592.32822

EXAMPLE 247 {4-[3-(Dimethylamino)propyl]-1-piperazinyl}{10-[(2,2′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0770] HRMS [(+)ESI, m/z]: 590.34875[M+H]⁺. Calcd. for C₃₇H′AN₅O₂:590.34896

EXAMPLE 248 {4-[3-(Dimethylamino)propyl]-1-piperazinyl}{10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0771] HRMS [(+)ESI, m/z]: 606.34364[M+H]⁺. Calcd. for C₃₇H₄₄N₅O₃:606.34387

EXAMPLE 249 {4-[3-(Dimethylamino)propyl]-1-piperazinyl}{10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0772] HRMS [(+)ESI, m/z]: 576.33344[M+H]⁺. Calcd. for C₃₆H₄₂N₅O₂:576.33331

EXAMPLE 250 {4-[3-(Dimethylamino)propyl]-1-piperazinyl}{10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0773] HRMS [(+)ESI, m/z]: 606.34409[M+H]⁺. Calcd. for C₃₇H₄₄N₅O₃:606.34387

EXAMPLE 251{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[3-(dimethylamino)propyl]-1-piperazinyl}methanone

[0774] HRMS [(+)ESI, m/z]: 640.30437[M+H]⁺. Calcd. for C₃₇H₄₃CIN₅O₃:640.30490

EXAMPLE 252{10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[3-(dimethylamino)propyl]-1-piperazinyl}methanone

[0775] HRMS [(+)ESI, m/z]: 656.29921[M+H]⁺. Calcd. for C₃₇H₄₃CIN₅O₄:656.29981

EXAMPLE 253 {4-[3-(Dimethylamino)propyl]-1-piperazinyl}{10-[3-methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0776] HRMS [(+)ESI, m/z]: 642.34363[M+H]⁺. Calcd. for C₄₀H₄₄N₅O₃:642.34387

EXAMPLE 254{10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[3-(dimethylamino)propyl]-1-piperazinyl}methanone

[0777] HRMS [(+)ESI, m/z]: 622.33914[M+H]⁺. Calcd. for C₃₇H₄₄N₅O₄:622.33879

EXAMPLE 255{10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[3-(dimethylamino)propyl]-1-piperazinyl}methanone

[0778] HRMS [(+)ESI, m/z]: 622.33845[M+H]⁺. Calcd. for C₃₇H₄₄N₅O₄:622.33879

EXAMPLE 256{10-[2-Chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[3-(dimethylamino)propyl]-1-piperazinyl}methanone

[0779] HRMS [(+)ESI, m/z]: 646.29385[M+H]⁺. Calcd. for C₃₉H₄₁CIN₅O₂:646.29433

EXAMPLE 257{10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[3-(dimethylamino)propyl]-1-piperazinyl}-methanone

[0780] HRMS [ESI(+), m/z: 644.32017[M+H]⁺. Calcd. for C₃₇H₄₁F₃N₅O₂:644.32069

EXAMPLE 258(10-{[2-Methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone

[0781] HRMS [(+)ESI, m/z]: 627.29381[M+H]⁺. Calcd. for C₃₇H₃₈F₃N₄O₂:627.29414

EXAMPLE 259{10-[(2′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone

[0782] HRMS [(+)ESI, m/z]: 589.31760[M+H]⁺. Calcd. for C₃₇H₄₁N₄O₃:589.31732

EXAMPLE 260{10-[(2,2′-Dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone

[0783] HRMS [(+)ESI, m/z]: 573.32214[M+H]⁺. Calcd. for C₃₇H₄₁N₄O₂:573.32241

EXAMPLE 261{10-[2-Chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone

[0784] HRMS [(+)ESI, m/z]: 629.26794[M+H]⁺. Calcd. for C₃₉H₃₈CIN₄O₂:629.26778

EXAMPLE 262{10-[3-Methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone

[0785] HRMS [(+)ESI, m/z]: 625.31761[M+H]⁺. Calcd. for C₄₀H₄₁N₄O₃:625.31732

EXAMPLE 263{10-[(3′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone

[0786] HRMS [(+)ESI, m/z]: 589.31770[M+H]⁺. Calcd. for C₃₇H₄₁N₄O₃:589.31732

EXAMPLE 264{10-[(2′-Methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone

[0787] HRMS [(+)ESI, m/z]: 559.30704[M+H]⁺. Calcd. for C₃rH₃₉N₄O₂:559.30676

EXAMPLE 265 ({10-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone

[0788] HRMS [(+)ESI, m/z]: 575.30152[M+H]⁺. Calcd. for C₃₆H₃₉N₄O₃:575.30167

EXAMPLE 266{10-[(2-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone

[0789] HRMS [(+)ESI, m/z]: 589.31773[M+H]⁺. Calcd. for C₃₇H₄₁N₄O₃:589.31732

EXAMPLE 267 {10-[(6-Chloro-3-methoxy-2′-methyl[,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone

[0790] HRMS [(+)ESI, m/z]: 623.27896[M+H]⁺. Calcd. for C₃₇H₄₀CIN₄O₃:623.27835

EXAMPLE 268{10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone

[0791] HRMS [(+)ESI, m/z]: 639.27238[M+H]⁺. Calcd. for C₃₇H₄₀CIN₄O₄:639.27326

EXAMPLE 269{10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone

[0792] HRMS [(+)ESI, m/z]: 605.31257[M+H]⁺. Calcd. for C₃₇H₄₁N₄O₄:605.31224

EXAMPLE 270{10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone

[0793] HRMS [(+)ESI, m/z]: 605.31209[M+H]⁺. Calcd. for C₃₇H₄₁N₄O₄:605.31224

EXAMPLE 271[(3R)-3-(Dimethylamino)pyrrolidinyl](10-{[2-methyl-2′-(trifluoromethyl)[1,¹′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)methanone

[0794] HRMS [(+)ESI, m/z]: 587.26200[M+H]⁺. Calcd. for C₃₄H₃₄F₃N₄O₂:587.26284

EXAMPLE 272 [(3R)-3-(Dimethylamino)pyrrolidinyl]{10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0795] HRMS [(+)ESI, m/z]: 549.28581[M+H]⁺. Calcd. for C₃₄H₃₇N₄O₃:549.28602

EXAMPLE 273{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(3R)-3-(dimethylamino)pyrrolidinyl]methanone

[0796] HRMS [(+)ESI, m/z]: 583.24837[M+H]⁺. Calcd. for C₃₄H₃₆CIN₄O₃:583.24705

EXAMPLE 274 [(3R)-3-(Dimethylamino)pyrrolidinyl]{10-[(2,2′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0797] HRMS [(+)ESI, m/z]: 533.29105[M+H]⁺. Calcd. for C₃₄H₃₇N₄O₂:533.29111

EXAMPLE 275{10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(3R)-3-(dimethylamino)pyrrolidinyl]methanone

[0798] HRMS [(+)ESI, m/z]: 599.24184[M+H]⁺. Calcd. for C₃₄H₃₆CIN₄O₄:599.24196

EXAMPLE 276 [(3R)-3-(Dimethylamino)pyrrolidinyl]{10-[3-methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0799] HRMS [(+)ESI, m/z]: 585.28535[M+H]⁺. Calcd. f6r C₃₇H₃₇N₄O₃:585.28602

EXAMPLE 277{10-[2-Chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(3R)-3-(dimethylamino)pyrrolidinyl]methanone

[0800] HRMS [(+)ESI, m/z]: 589.23703[M+H]⁺. Calcd. for C₃₆H₃₄CIN₄O₂:589.23648

EXAMPLE 278[(3R)-3-(Dimethylamino)pyrrolidinyl]{10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0801] HRMS [(+)ESI, m/z]: 549.28594[M+H]⁺. Calcd. for C₃₄H₃₇N₄O₃:549.28602

EXAMPLE 279 [(3R)-3-(Dimethylamino)pyrrolidinyl]{10-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0802] HRMS [(+)ESI, m/z]: 535.27042[M+H]⁺. Calcd. for C₃₃H₃₅N₄O₃:535.27037

EXAMPLE 280 [(3R)-3-(Dimethylamino)pyrrolidinyl]{10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0803] HRMS [(+)ESI, m/z]: 519.27502[M+H]⁺. Calcd. for C₃₃H₃₅N₄02:519.27546

EXAMPLE 281 [(3R)-3-(Dimethylamino)pyrrolidinyl]{10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0804] HRMS [(+)ESI, m/z]: 549.28607[M+H]⁺. Calcd. for C₃₄H₃₇N₄O₃:549.28602

EXAMPLE 282 {10-[(2,2′-Dimethoxy[1,1¹′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl][(3R)-3-(dimethylamino)pyrrolidinyl]methanone

[0805] HRMS [(+)ESI, m/z]: 565.28071[M+H]⁺. Calcd. for C₃₄H₃₇N₄O₄:565.28094

EXAMPLE 283{10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(3R)-3-(dimethylamino)pyrrolidinyl]methanone

[0806] HRMS [(+)ESI, m/z]: 565.28058[M+H]⁺. Calcd. for C H₃₇N₄O₄:565.28094

EXAMPLE 284 N-[(1S)-2-Amino-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0807] HRMS [(+)ESI, m/z]: 627.23303[M+H]⁺. Calcd. for C H₃₀F₃N₆O₃:627.23260

EXAMPLE 285 N-[(1S)-2-Amino-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-10-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0808] HRMS [(+)ESI, m/z]: 575.23897[M+H]⁺. Calcd. for C₃₃H₃₁N₆O₄:575.24013

EXAMPLE 286 N-[(1S)-2-Amino-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-10-[(2,2′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0809] HRMS [(+)ESI, m/z]: 605.24974[M+H]⁺. Calcd. for C₃₄H₃₃N₆O₅:605.25070

EXAMPLE 287 N-[(1S)-2-Amino-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-10-[(6-chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0810] HRMS [(+)ESI, m/z]: 639.21102[M+H]⁺. Calcd. for C₃₄H₃₂CIN₆O₅:639.21173

EXAMPLE 288 N-[(lS)-2-Amino-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-10-[(2′-methoxy-2-methyl[1,1′-biphenyl]4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0811] HRMS [(+)ESI, m/z]: 589.25637[M+H]⁺. Calcd. for C₃₄H₃₃N60₄:589.25578

EXAMPLE 2891H-Imidazol-1-yl-{10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0812] HRMS [(+)ESI, m/z]: 503.20731[M+H]⁺. Calcd. for C₃₁ H₂₇N₄O₃:503.20777

EXAMPLE 2901H-Imidazol-1-yl-{10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0813] HRMS [(+)ESI, m/z]: 503.20834[M+H]⁺. Calcd. for C₃₁H₂₇N₄O₃:503.20777

EXAMPLE 2911H-Imidazol-1-yl-{10-[3-methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0814] HRMS [(+)ESI, m/z]: 539.20754[M+H]⁺. Calcd. for C₃₄H₂₇N₄O₃:539.20777

EXAMPLE 2921H-Imidazol-1-yl-{10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0815] HRMS [(+)ESI, m/z]: 503.20760[M+H]⁺. Calcd. for C₃₁H₂₇N₄O₃:503.20777

EXAMPLE 293{10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(1H-imidazol-1-yl)methanone

[0816] HRMS [(+)ESI, m/z]: 519.20285[M+H]⁺. Calcd. for C₃₁H₂₇N₄O₄:519.20269

EXAMPLE 2941H-Imidazol-1-yl(10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)methanone

[0817] HRMS [(+)ESI, m/z]: 541.18438[M+H]⁺. Calcd. for C₃₁H₂₄F₃N₄O₂:541.18459

EXAMPLE 295N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0818] HRMS [(+)ESI, m/z]: 561.28517[M+H]⁺. Calcd. for C₃₅H₃₇N₄O₃:561.28602

EXAMPLE 296N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-10-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0819] HRMS [(+)ESI, m/z]: 547.26933[M+H]⁺. Calcd. for C₃₄H₃₅N₄O₃:547.27037

EXAMPLE 297N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-10-[(6-chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0820] HRMS [(+)ESI, m/z]: 595.24661[M+H]⁺. Calcd. for C₃₅H₃₆CIN₄O₃:595.24705

EXAMPLE 298N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yi]-10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0821] HRMS [(+)ESI, m/z]: 561.28489[M+H]⁺. Calcd. for C₃₅H₃₇N₄O₃:561.28602

EXAMPLE 299N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-10-[(2,2′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0822] HRMS [(+)ESI, m/z]: 577.28113[M+H]⁺. Calcd. for C₃₅H₃₇N₄O₄:577.28094

EXAMPLE 300N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-10-[(2,2′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0823] HRMS [(+)ESI, m/z]: 577.28101[M+H]⁺. Calcd. for C₃₅H₃₇N₄O₄:577.28094

EXAMPLE 301N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0824] HRMS [(+)ESI, m/z]: 599.26211[M+H]⁺. Calcd. for C₃₅H₃₄F₃N₄O₂:599.26284

EXAMPLE 302 tert-Butyl (5S)-6-amino-5-[({10-[(6-chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}carbonyl)amino]-6-oxohexylcarbamate

[0825] HRMS [(+)ESI, m/z]: 730.29945[M+H]⁺. Calcd. for C₃₉H₄₅CIN₅O₇:730.30021

EXAMPLE 303 tert-Butyl (5S)-6-amino-5-[({10-[(2,2′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}carbonyl)amino]-6-oxohexylcarbamate

[0826] HRMS [(+)ESI, m/z]: 696.33935[M+H]⁺. Calcd. for C₃₉H₄₆N₅O₇:696.33918

EXAMPLE 304 tert-Butyl (5S)-6-amino-5-[({10-[(6-chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}carbonyl)amino]-6-oxohexylcarbamate

[0827] HRMS [(+)ESI, m/z]: 714.30505[M+H]⁺. Calcd. for C₃₉H₄₅CIN₅0r:714.30529

EXAMPLE 305{10-(3-Methoxy-4-pyridin-3-y1-benzoyl)-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepin-3-yi}-[4-(1-piperidinyl)-1-piperidinyl]-methanoneMS [(+)ESI, m/z]: 590[M+H]⁺. Calcd. for C₃₆H₄₀N₅O₃: 590.313

[0828] The following examples were prepared according to the GeneralProcedure L described below.

[0829] General Procedure L

[0830] Step A. To a stirred cooled (0° C.) solution of an appropriatelysubstituted 10-(4-amino)benzoyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (10 mmol) in dichloromethane (20 mL) wasadded N,N-diisopropylethyl amine (2.09 mL, 12 mmol) followed by theaddition of 9-fluorenylmethyl chloroformate (2.85 g, 11 mmol) in oneportion. The reaction was allowed to warm to room temperature. TLCanalysis was used to monitor the progress of the reaction and after 8hours, indicated that a single product was formed. The reaction mixturewas diluted with dichloromethane and washed with water and brine. Theorganic phase was dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting residue was purified by flash columnchromatography (Biotage Flash 40S, gradient elution from 10 to 20% ethylacetate in hexanes) to provide the desired appropriately substituted4-(fluorenylmethoxycarbonyl) -10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine.

[0831] Step B. Trichloroacetyl chloride (3.35 mL, 30 mmol) was added toa solution of an appropriately substituted4-(fluorenylmethoxycarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step A (10 mmol) and N,N-diisopropylethylamine (3.48 mL, 20 mmol) in dichloromethane, and the solution wasstirred at ambient temperature for 2 hours. An aqueous solution ofsodium bicarbonate (0.5 M) was added to the mixture and the organiclayer was separated, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was dissolved in a solution of piperidine inN,N-dimethyl formamide (20%, v/v) and stirred until the startingmaterial was no longer observed by HPLC/TLC analysis. The mixture wasdiluted with ethyl acetate and washed with water. The organic phase wasdried over anhydrous sodium sulfate, filtered and concentrated. Thedesired appropriately substituted2,2,2-trichloro-1-[10-(4-aminobenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}-ethanone was isolated by flashchromatography (Biotage, Flash 40M, gradient elution from 20 to 30%ethyl acetate in hexanes).

[0832] Step C. An appropriately substituted 1,4-diketone (25 mmol) wasadded to a vial containing an appropriately substituted aniline of StepB (4.4 mmol) followed by the addition of acetic acid (1 mL). Thecontents of the vial were stirred and heated (80° C.) without the vialcapped (to allow for the removal of water). After 1 hour the solutionwas diluted with ethyl acetate (20 mL). The organic phase was washedwith water, aqueous sodium bicarbonate and brine. The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated. Theresulting residue was purified by flash column chromatography to affordthe desired appropriately substituted2,2,2-trichloro-1-10-4-(1H-pyrrol-1-yl)-benzoyl]-10,11-dihydro[2,1-c][1,4]benzodiazepin-3-yl}-ethanone.

[0833] Step D. The material from Step C (3.85 mmol) was dissolved intetrahydrofuran (10 mL) and treated with aqueous sodium hydroxide (2 N,3 mL). The mixture was allowed to stir with heating (80° C.) overnight.After cooling to room temperature, aqueous hydrochloric acid (2 N, 3.2mL) was added and product was recovered by extraction with ethylacetate. The combined extracts were evaporated and the residue purifiedby flash column chromatography, eluting with a gradient of 20 to 50%ethyl acetate in hexanes to provide the desired appropriatelysubstituted title compound.

EXAMPLE 306{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone

[0834] HRMS [(+)ESI, m/z]: 538.28136[M+H]⁺. Calcd. for C₃₂H₃₆N₅O₃:538.28127

EXAMPLE 307{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone

[0835] HRMS [(+)ESI, m/z]: 552.29613[M+H]⁺. Calcd. for C₃₃H₃₈N₅O₃:552.29692

EXAMPLE 308N-[3-(Dimethylamino)propyl]-10-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0836] HRMS [(+)ESI, m/z]: 540.29503[M+H]⁺. Calcd. for C₃₂H₃8N₅O₃:540.29692

EXAMPLE 309N-[2-(Dimethylamino)ethyl]-10-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0837] HRMS [(+)ESI, m/z]: 540.29642[M+H]⁺. Calcd. for C₃₂H₃₈N₅O₃:540.29692

EXAMPLE 310 N-[3-(Dimethylamino)propyl]-10-[4-(2,5-dimethyl-iH-pyrrol-1-yl)-3-methoxybenzoyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0838] HRMS [(+)ESI, m/z]: 554.31172[M+H]⁺. Calcd. for C₃₃H₄₀N₅O₃:554.31257

EXAMPLE 311{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxy-benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]-methanone

[0839] HRMS [(+)ESI, m/z]: 606.34354[M+H]⁺. Calcd. for C₃₇H₄₄N₅O₃:606.34387

EXAMPLE 31210-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-N-[3-(1H-imidazol-1-yl)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0840] HRMS [(+)ESI, m/z]: 563.27492[M+H]⁺. Calcd. for C₃₃H₃₅N₆O₃:563.27652

EXAMPLE 313{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone

[0841] HRMS [(+)ESI, m/z: 592.32816[M+H]⁺. Calcd. for C₃₆H₄₂N₅O₃:592.32822

EXAMPLE 31410-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0842] HRMS [(+)ESI, m/z]: 566.31192[M+H]⁺. Calcd. for C₃₄H₄₀N₅O₃:566.31257

EXAMPLE 31510-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0843] HRMS [(+)ESI, m/z: 566.31226[M+H]⁺. Calcd. for C₃₄H₄₀N₅O₃:566.31257

EXAMPLE 316 {4-[2-(Dimethylamino)ethyl]-1-piperazinyl}{10-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0844] HRMS [(+)ESI, m/z]: 595.33898[M+H]⁺. Calcd. for C₃₅H₄₃N₆O₃:595.33912

EXAMPLE 317{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone

[0845] HRMS [(+)ESI, m/z]: 637.34914[M+H]⁺. Calcd. for C₃₇H₄₅N₆O₄:637.34968

EXAMPLE 318 (4-Allyl-1-piperazinyl){10-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0846] HRMS [(+)ESI, m/z]: 564.29788[M+H]⁺. Calcd. for C₃₄HwN₅O₃:564.29692

EXAMPLE 319{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-isopropyl-1-piperazinyl)methanone

[0847] WAC-510342

[0848] HRMS [(+)ESI, m/z]: 566.31184[M+H]⁺. Calcd. for C₃₄H₄₀N₄O₃:566.31257

EXAMPLE 320 {4-[3-(Dimethylamino)propyl]-1-piperazinyl}{10-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0849] HRMS [(+)ESI, m/z]: 609.35380[M+H]⁺. Calcd. for C₃₆H₄₅N₆O₃:609.35477

EXAMPLE 321{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone

[0850] HRMS [(+)ESI, m/z]: 592.32768[M+H]⁺. Calcd. for C₃₆H₄₂N₅O₃:592.32822

EXAMPLE 322[(3R)-3-(Dimethylamino)pyrrolidinyl]{10-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0851] HRMS [(+)ESI, m/z]: 552.29598[M+H]⁺. Calcd. for C₃₃H₃₈N₅O₃:552.29692

EXAMPLE 323 [3-(4-Methyl-piperazine-1-carbonyl)-4H-10H-3a,5,9-triaza-benzo[flazulen-9-yl]-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-methanone

[0852] Step A. 2-Chloromethyl-pyridine-3-carboxylic acid methyl ester

[0853] A solution of methyi 2-methyinicotinate (20.0 g, 0.132 mol) andtrichloroisocyanuric acid (46.0 g, 0.198 mol) in dichloromethane (100mL) was stirred at room temperature overnight. The reaction mixture wasthen washed with saturated aqueous sodium carbonate and saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered, and the solvent evaporated in vacuo to provide the titlecompound as a yellow liquid (11. 2 g), which is used as such in the nextstep.

[0854] Step B. 2-(2-Formyl-pyrrol-1-ylmethyl)-pyridine-3-carboxylic acidmethyl ester

[0855] To a suspension of sodium hydride (5.8 g, 0.12 mol) in dryN,N-dimethyl formamide (25 mL) was added slowly under nitrogen asolution of pyrrole 2-carboxaldehyde (10.5 g, 0.11 mol) inN,N-dimethylformamide (10 mL), and the reaction mixture was stirred atroom temperature for 30 minutes. The reaction was then cooled to 5° C.and 2-chloromethyl-pyridine-3-carboxylic acid methyl ester of Step A wasadded slowly, the temperature being maintained at or below 20° C. Afterthe addition was complete, the reaction was stirred at room temperaturefor 30 minutes. The mixture was evaporated to dryness, and the residuewas dissolved in ethyl acetate (250 mL). This solution was washed withwater and dried over anhydrous magnesium sulfate. The solvent was thenremoved in vacuo leaving a dark crystalline solid (23.4 g), which waspurified by chromatography on silica gel eluting with a gradient ofethyl acetate/petroleum ether to provide the title compound as a tancrystalline solid (13.75 g), m.p. 91-93° C.

[0856] Step C. 1-(3-Phenacetyl-pyridin-2-yl methyl)carbamic acid benzylester

[0857] To a stirred solution of2-(2-formyl-pyrrol-1-ylmethyl)-pyridine-3-carboxylic acid methyl esterof Step B (13.65 g, 55.9 mmol) in methanol (50 mL) was added sodiumhydroxide (2.2 g, 55.9 mmol.). The reaction mixture was refluxed undernitrogen for 2 hours, and then the solvent was removed in vacuo. Aportion of the residual yellow solid (5 g) was suspended in a mixture ofbenzyl alcohol (20 mL) and benzene (30 mL). Diphenylphosphoryl azide(6.54 g, 1.2 equiv.) was added, and the reaction was slowly heated toreflux. After refluxing for 1 hour, the mixture was cooled and washedwith water, dried over anhydrous magnesium sulfate, filtered andevaporated to dryness to provide the title compound as a tan crystallinesolid (4.4 g), m.p. 109-111° C.

[0858] Step D. 9,10-Dihydro-4H-3a, 5,9-triaza-benzo[f]azulene

[0859] A stirred mixture of 1-(3-phenacetyl-pyridin-2-ylmethyl)-carbamic acid benzyl ester of Step C (1.0 g), in ethyl acetate(10 mL) containing 10% palladium on charcoal (10 mg.), magnesium sulfate(0.010 g) and 5 drops of acetic acid was hydrogenated at atmosphericpressure until hydrogen uptake ceased. The reaction mixture was thenfiltered through Celite and the solvent removed in vacuo. The crudeproduct (yellow crystalline solid, 0.530 g) was purified bychromatography on silica gel eluting with a gradient of ethyl acetate inpetroleum ether to provide the title product as a yellow crystallinesolid, m.p. 171-172° C.

[0860] Step E. (4-Bromo-3-methyl-phenyl)-(4H, 1OH-3a,5,9-triaza-benzo[flazulen-9-yl) -methanone

[0861] To a stirred solution of the 9,10-dihydro-4H-3a,5,9-triaza-benzo[flazulene of Step D (1.0 g) in dichloromethane (10 mL)was added 3-methyl-4-bromobenzoyl chloride (1.39 g) and triethylamine(1.1 mL). After stirring for 2.5 hours, the reaction mixture was washedwith water, dried over anhydrous magnesium sulfate, filtered and thesolvent removed in vacuo to provide the title product as a tancrystalline solid (2.3 g), which was used without further purification.

[0862] Step F. (2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-(4H,10H-3a, 5,9-triaza -benzo[flazulen-9-yl)-methanone

[0863] A stirred mixture of (4-bromo-3-methyl-phenyl)-(4H, 1OH-3a,5,9-triaza -benzo[flazulen-9-yl)-methanone of Step E (1.0 g),2-trifluoromethyl-boronic acid (1.49 g, 3.0 equiv.), potassium phosphate(2.2 g) and a catalytic amount (0.050 g) of tetrakis(triphenylphosphine)palladium (0) in dioxane (10 mL) was refluxed for 2 hours. The solventwas then removed in vacuo and the residue dissolved in dichloromethane.The solution was then washed with water, dried over anhydrous magnesiumsulfate, filtered and evaporated to dryness. The residue was thenchromatographed on silica gel eluting with 5% ethyl acetate indichloromethane to yield a colorless gum which crystallized uponaddition of a little diethyl ether to provide the title compound as acream-colored crystalline solid (0.500 g), m.p. 153-155° C.

[0864]¹H NMR (DMSO-d₆, 400 MHz): δ1.85 (s, 3H), 5.10 (s, 2H), 5.40 (s,2H), 5.90 (t, 1H), 6.00 (s, 1H), 6.90 (t, 1H), 6.94 (d, 1H), 7.03 (d,1H), 7.12 (dd, 1H), 7.23 (d, 1H), 7.28 (s, 1H), 7.37 (d, 1H), 7.58 (t,1H), 7.68 (t, 1H), 7.80 (d, 1H), 8.27 (d, 1H) MS [(+)ESI, m/z]:448[M+H]⁺.

[0865] Anal. Calcd. for C₂₆H₂₀F₃N₃O: C, 69.79, H, 4.51, N, 9.39. Found:C, 69.91, H, 4.30, N, 9.26)

[0866] Step G.2,2,2-Trichloro-1-{[9-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-9,10-dihydro-4H-3a,5,9-triaza-benzo[flazulen-3-yl}-ethanone

[0867] To a solution of(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-(4H, 10H-3a,5,9-triaza-benzo[f]azulen-9-yl)-methanone in methylene chloride wasadded trichloroacetyl chloride (1.1 equiv.) and triethylamine (1.5equiv,) After stirring overnight at room temperature, the reaction waswashed with water, dried over anhydrous magnesium sulfate, andevaporated to dryness to provide the crude title compound which was usedas such in the next step.

[0868] Step H.9-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4yl)carbonyl]-9,10-dihydro-3a,5,9-triaza-benzo[flazulen-3-carboxylic acid

[0869] To a solution of2,2,2-trichloro-1-{[9-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-9,10-dihydro-4H-3a,5,9-triaza-benzo[flazulen-3-yl}-ethanone of Step G in acetone was added2.5 N sodium hydroxide (1.0 equiv.). After stirring ovemight, thesolvent was removed in vacuo leaving the crude sodium salt of thecarboxylic acid. This was dissolved in anhydrous ethanol and treatedwith 2 N hydrochloric acid (1.0 equiv.). The solvent was removed invacuo, the residue redissolved in anhydrous ethanol and the solventagain removed in vacuo. The crude title compound was then dried in vacuoover phosphorus pentoxide.

[0870] Step I. [3-(4-Methyl-piperazine-1-carbonyl)-4H-10H-3a,5,9-triaza-benzo[flazulen-9-yl]-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-methanone

[0871] To a solution of the9-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4yl)carbonyl]-9,10-dihydro-3a,5,9-triaza-benzo[f]azulen-3-carboxylic acid (3.38 mmol) of Step H inN,N-dimethylformamide (20 mL) was added 1-hydroxybenzotriazole (1.1equiv.) and [3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(1.2 equiv. ), followed by 4-methyl-piperazine (1.2 equiv.) andN,N-diisopropylethyl amine (1.5 equiv.). The reaction mixture wasstirred overnight, then diluted with ethyl acetate and washed with waterand saturated aqueous sodium bicarbonate. The organic phase was driedover anhydrous sodium sulfate, filtered and concentrated in vacuo.Purification of the residue was effected by chromatography on silica geleluting with a gradient of methanol in ethyl acetate to provide thetitle compound as a white foam.

What is claimed:
 1. A compound of the formula:

R₁ and R₂ are, independently, selected from hydrogen, (C₁-C₈)loweralkyl, halogen, cyano, trifluoromethyl, hydroxy, amino, (C₁-C₆) loweralkylamino, (C₁-C₆) lower alkoxy, —OCF₃, (C₁-C₆) lower alkoxy carbonyl,—NHCO[(C₁-C₆)lower alkyl], carboxy, —CONH₂, —CONH[(C₁-C₆) lower alkyl],or —CON[(C₁-C₆) lower alkyl]₂; R₃ is a substituent selected fromhydrogen, (C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy, hydroxy, amino,(C₁-C₆) lower alkylamino, —CO lower alkyl (C₁-C₆), or halogen;R₄consists of the moiety B-C; wherein: B is selected from the group of:

wherein: A is CH or N; R₅, R₆, R₇, R₈, R₉, Rl₀ are, independently,selected from hydrogen, (C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy,(C₁-C₆) lower alkyl carbonyl, (C₃-C₆) lower alkenyl, (C₃-C₆) loweralkynyl, hydroxy (C₁-C₆) lower alkyl, alkoxy (C₁-C₆) lower alkyl,acyloxy (C₁-C₆) lower alkyl, (C₃-C₈) cycloalkyl, formyl,cycloalkylcarbonyl, carboxy, lower alkoxy carbonyl,cycloalkyloxycarbonyl, aryl alkyloxycarbonyl, carbamoyl, —O— CH₂—CH═CH₂,halogen, halo lower alkyl, trifluoromethyl, —OCF₃, —S[(C₁-C₆) loweralkyl], —OC(O)N[(C, —C₆) lower alkyl]₂, —CON H [(C, —C₆) lower alkyl],—CON[(C, —C₆) lower alkyl]₂, (C₁-C₆) lower alkylamino, di-[(C₁-C₆) loweralkyl]amino, (C₁-C₆) lower alkyl di-[(C₁-C₆) lower alkyl]amino, hydroxy,cyano, trifluoromethylthio, nitro, amino, (C₁-C₆) lower alkylsulfonyl,aminosulfonyl, (C₁-C₆) lower alkylaminosulfonyl,

phenyl or naphthyl; and R is selected from —OH, NHOR₃₆, or any of thefollowing groups:

wherein: R₁, and R₁₂ are, independently, selected from hydrogen, (C₁-C₆)lower alkyl, (C₃-C₆) lower alkenyl, (C₃-C₈) cycloalkyl optionallymono-or di-[(C₁-C₆) loweralkyl] substituted, bicycloalkyl including butnot limited to adamantanyl, adamantane lower alkyl, bornyl, norbornyl,or quinuclidyl;

cycloalkyl lower alkyl, halo lower alkyl, cyano lower alkyl, lower alkylthiol, alkoxycarbonyl lower alkyl, alkylthio lower alkyl, indolyl loweralkyl; aryl, optionally substituted with 1 to three substituentsselected from the group of lower alkyl, hydroxy, (C₁-C₆) lower alkoxy,aryl lower alkoxy, halogen, —CF₃, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃,—OCF₂CF₃, —OCH₂CHF₂, alkylamido lo wer alkyl, dialkylamido 15 loweralkyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, —SCF₃,—SO₂[lower alkyl], sulfonyl cycloalkyl,

or (C₇-C₁₂) aryl lower alkyl, wherein the aryl mo iety is optionallysubstituted with halogen or alkoxy; with the proviso that R₁₁, and R₁₂can be taken together with the nitrogen to which they are attached toform an unsaturated heteroaromatic ring containing 2 nitrogen atoms; R₁₃is selected from hydrogen, (C₁-C₆) lower alkyl, (C₇-Ci2) lower aralkyl,or—(CH₂)_(p)—N(lower alkyl)₂; R₁₄ and R₁₅ are, independently, selectedfrom hydrogen, (C₁-C₆) lower alkyl, or (C₇-C₁₂) aryl lower alkyl, withthe proviso that R₁₄ and R₁₅ can be taken together with the nitrogenatom to which they are attached to form a 5 to 7 membered saturatedheterocycle, optionally containing one additional O or S atom (all ofthe above rings being optionally substituted with 1 or more alkylgroups); or a 5-membered unsaturated heterocycle containing 1 to 3nitrogen atoms; R₁₆ and R₁₇ are, independently selected from the groupof hydrogen, (C₁-C₆) lower alkyl, [(C₁-C₆) lower alkyl]₂, (C₇-C₁₂) aryllower alkyl, lower alkoxy carbonyl, aryl lower alkoxy carbonyl, —CONH₂,—CONH [(C₁-C₆) lower alkyl], —CON [(C₁-C₆) lower alkyl]₂;cycloalkylamino (C₁-C₆) lower alkyl, [(C₁-C₆) lower alkyl]₂ amino; withthe proviso that R₁₆ and R₁ ₇ can be joined to form a 5 to 6 memberedsaturated ring to provide a bicyclic system, optionally containing oneor more alkyl groups including, but not limited to,1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane; R₁₈ is one to threesubstituents selected independently from the group of hydrogen, or(C₁-C₆) lower alkyl; R₁₉ is selcted from the group of hydrogen, (C₁-C₈)lower alkyl, —N[(C₁-C₆) lower alkyl]₂, or cycloalkylamine when Y′=CH₂;or it is selected from the group of hydrogen and (C₁-C₆) lower alkylwhen Y′=X′; R₂₀ is selected from the group of hydrogen, (C₁-C₆) loweralkyl, (C₃-C₆) lower alkenyl, (C₃-C₆) lower alkynyl, (C₃-C₈) cycloalkyl,—CONH₂, —CON[lower alkyl]₂, carbonyl lower alkyl, lower alkyl CONH[loweralkyl], lower alkyl CON[lower alkyl]₂, cycloalkylamino carbonyl,cycloalkylamino carbonyl lower alkyl, arylamino carbonyl lower alkyl,lower alkoxy carbonyl, lower alkoxy carbonyl lower alkyl,—(CH₂)_(p)—N[lower alkyl]₂, —(CH₂)_(p)—N[lower alkenyl]₂, —CH[aryl]₂wherein the aryl is optionally substituted by (C₁-C₆) lower alkyl,C₁-C₆) lower alkoxy, or halogen;

benzodioxolyl, benzodioxolyl lower alkyl, benzodioxanyl, benzodioxanyllower alkyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,furancarbonyl, —SO₂[lower alkyl], aryl optionally substituted by one tothree substituents selected independently, from the group of hydrogen,halogen, (C₁-C₆) lower alkyl, (C₃-C₆) lower alkenyl, (C₃-C₈) loweralkynyl, lower alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F, —OCF₂CF₃,—OCH₂CHF₂, —CO lower alkyl, —CN, nitro, —SCH₃, aryl lower alkoxy, aryllower alkoxy carbonyl, indolyl, morpholino or thiomorpholino; or (C₇-C₂) lower aralkyl wherein the aryl moiety is optionally substituted withhalogen, (C₁-C₆) lower alkyl, or (C₁-C₆) lower alkoxy; R₂₁ and R₂₂ areselected, independently, from the group of hydrogen, (C₁-C₆) loweralkyl, or (C₇-C₁₂) aryl lower alkyl; R₂₃ is selected from hydrogen, or(C₁-C₆) lower alkyl; R₂₄ is selected from the group of (C₁-C₆) loweralkyl, (C₇C₁₂) aryl lower alkyl, lower alkoxycarbonyl, or SO₂[(C₁-C₆)lower alkyl]; R₂₅ is selected from (C₁-C₆) lower alkyl, (C₇-C₁₂) aryllower alkyl, lower alkoxycarbonyl, aryl lower alkoxycarbonyl, —COOH,—CONH₂, —CONH[(C₁-C₆) lower alkyl], —CON H[(C₇-C₁₂) aryl lower alkyl],—CON[(C₁-C₆) lower alkyl]₂, or —CON[(C₇-C₁₂) aryl lower alkyl]₂; R₂₆ isselected from hydrogen, lower alkoxycarbonyl, fluorenylalkoxycarbonyl,aryl lower alkyl, or aryl lower alkoxycarbonyl; R₂₇ and R₂₈ are,independently, selected from the group of hydrogen, lower alkyl, aryllower alkyl (the aryl moiety being optionally substituted by hydroxy,alkoxy, or halogen), or

with the proviso that R₂₇ and R₂₈ can be taken together with the carbonto which they are attached to form a 3 to 6-membered saturated ring; R₂₉and R₃₀ are, independently, selected from the group of hydrogen, (C₁-C₆)lower alkyl, (C₃-C₆) lower alkenyl, (C₃-C₆) lower alkynyl, cyclo loweralkyl, or aryl [optionally substituted by hydroxy, (C₁-C₆) lower alkoxy,(C₁-C₆) lower alkyl, halo, cyano, —SO₂[(C₁-C₆) lower alkyl, or—S[(C₁-C₆) lower alkyl]; R₃₁ is selected from the group of hydroxy,(C₁-C₆) lower alkoxy, aryl lower alkoxy, amino, —NH[(C₁-C₆) loweralkyl], or —N[(C₁-C₆) lower alkyl]₂; R₃₂ is selected from the group ofhydrogen, or (C₁-C₆) lower alkyl; R₃₃ is one to three substituentsselected from the group of hydrogen, or (C₁-C₆) lower alkyl; R₃₄ andR₃₅, are, independently, selected from the group of hydrogen, (C₁-C₆)lower alkyl, (C₇-C₁₂) aryl lower alkyl, with the proviso that R₃₄ andR₃₅ taken together with the nitrogen atom to which they are attached,may form a 4 to 8 membered saturated heterocycle, optionally containingone additional O, S or N[(C₁-C₆) lower alkyl], all the above rings beingoptionally substituted with 1 or more alkyl groups; or a 5 memberedunsaturated heterocycle containing 2 to 3 nitrogen atoms; R₃₆ isselected from the group of hydrogen, or (C₁-C₆) lower alkyl; X′ is O, S,SO, SO₂; Y′=CH₂ or X′; K=Y′ or N[(C₁-C₆) lower alkyl]; m is an integerfrom 1 to 4; n is an integer from 1 to 4; p is an integer from 2 to 4; qis an integer from 1 to 5; r is an integer from 1 to 2; s is an integerfrom 0 to 1; and the pharmaceutically acceptable salts, or pro-drugforms thereof.
 2. A compound having the formula:

R₁ and R₂ are, independently, selected from hydrogen, (C₁-C₆)loweralkyl, halogen, cyano, trifluoromethyl, hydroxy, amino, (C₁-C₆) loweralkylamino, (C₁-C₆) lower alkoxy, —OCF₃, (C₁-C₆) lower alkoxy carbonyl,—NHCO[(C₁-C₆)lower alkyl], carboxy, —CONH₂, —CONH[(C₁-C₆) lower alkyl],or —CON[(C₁-C₆) lower alkyl]₂; R₃ is a substituent selected fromhydrogen, (C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy, hydroxy, amino,(C₁-C₆) lower alkylamino, —CO lower alkyl (C₁-C₆), or halogen; R₄consists of the moiety B-C; wherein: B is selected from the group of:

wherein: A is CH or N; R₅, R₆, R₇, R₈, R₉, R₁₀ are independentlyselected from hydrogen, (C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy,(C₁-C₆) lower alkyl carbonyl, (C₃-C₆) lower alkenyl, (C₃-C₆) loweralkynyl, hydroxy (C₁-C₆) lower alkyl, alkoxy(C₁-C₆) lower alkyl,acyloxy(C₁-C₆) lower alkyl, (C₃-C₈) cycloalkyl, formyl,cycloalkylcarbonyl, carboxy, lower alkoxy carbonyl,cycloalkyloxycarbonyl, carbamoyl, —O—CH₂—CH═CH₂, halogen, halo loweralkyl, trifluoromethyl, —OCF₃, —S[(C₁-C₆) lower alkyl], —OC(O)N[(C₁-C₆)lower alkyl]₂, —CONH[(C₁-C₆) lower alkyl], —CON[(C₁-C₆) lower alkyl]₂,(C₁-C₆) lower alkylamino, di-[(C₁-C₆) lower alkyl]amino, (C₁-C₆) loweralkyl di-[(C₁-C₆) lower alkyl]amino, hydroxy, cyano,trifluoromethylthio, nitro, amino, (C₁-C₆) lower alkylsulfonyl,aminosulfonyl, or (C₁-C₆) lower alkylaminosulfonyl; R₂₉ and R₃₀ are,independently, selected from the group of H, C₁-C₆ alkyl, (C₃-C₆) loweralkenyl, C₃-C₆ alkynyl, or cyclo C₃-C₆ alkyl; R is selected from loweralkyl, —NHNH₂, —NHOR₃₁; or —CH═CH—N[R₃₂]₃; lower alkoxy; phenyloptionally substituted by from one to three substituents selected from(C₁-C₆) lower alkyl or halogen ; or a moiety of the formulae:

R₁₁ and R₁₂ are, independently, selected from hydrogen, (C₁-C₆) loweralkyl, (C₃-C₆) lower alkenyl, (C₃-C₈) cycloalkyl optionally mono-ordi-[(C₁-C₆) loweralkyl]substituted, cycloalkyl lower alkyl, halo loweralkyl, cyano lower alkyl, lower alkyl thiol, alkoxycarbonyl lower alkyl,or alkylthio lower alkyl; or a moiety of the formulae:

R₁₃ is selected from hydrogen, (C₁-C₆) lower alkyl, (C₇-C₁₂) loweraralkyl, or—(CH₂)_(p)—N(lower alkyl)₂; R₁₄ and R₁₅ are, independently,selected from hydrogen, (C₁-C₆) lower alkyl, with the proviso that R₁₄and R₁₅ can be taken together with the nitrogen atom to which they areattached to form: a) a 5 to 7 membered saturated heterocycle, optionallysubstituted with 1 or more alkyl groups; or b) a 5-membered unsaturatedheterocycle containing 1 to 3 nitrogen atoms; R₁₈ is one to threesubstituents selected independently from the group of hydrogen, or(C₁-C₆) lower alkyl; R₁₉ is selcted from the group of hydrogen, (C₁-C₆)lower alkyl, —N[(C₁-C₆) lower alkyl]₂, or cycloakylamine when Y′=CH₂; orit is selected from the group of hydrogen and (C₁-C₆) lower alkyl whenY′=X′; R₂₀ is selected from the group of hydrogen, (C₁-C₆) lower alkyl,(C₃-C₆) lower alkenyl, (C₃-C₆) lower alkynyl, (C₃-C₈) cycloalkyl,—CONH₂, —CON[lower alkyl]₂, carbonyl lower alkyl, lower alkyl CONH[loweralkyl], lower alkyl CON[lower alkyl]₂, lower alkoxy carbonyl,(CH₂)_(p)—N[lower alkyl]₂, —(CH₂)_(p)—N[lower alkenyl]₂, —CH[phenyl]₂wherein the phenyl ring is optionally substituted by (C₁-C₆) loweralkyl, C₁-C₆) lower alkoxy, or halogen; or R₂₀ is a moiety of theformula:

R₂₁ and R₂₂ are selected, independently, from the group of hydrogen,(C₁-C₆) lower alkyl, or (C₇-C₁₂) aryl lower alkyl; R₂₃ is selected fromhydrogen, cyano or (C₁-C₆) lower alkyl; R₂₄ is selected from the groupof (C₁-C₆) lower alkyl, lower alkoxycarbonyl, or SO₂[(C₁-C₆) loweralkyl]; R₂₅ is selected from (C₁-C₆) lower alkyl, lower alkoxycarbonyl,—COOH, —CONH₂, —CONH[(C₁-C₈)lower alkyl)], or —CON[(C₁-c₆)loweralkyl)]₂; R₂₆ is selected from hydrogen, lower alkoxycarbonyl, orfluorenylalkoxycarbonyl; R₂₇ and R₂₈ are, independently, selected fromthe group of hydrogen or lower alkyl; with the proviso that R₂₇ and R₂₈can be taken together with the carbon to which they are attached to forma 3 to 6-membered saturated ring; R₃₁ is selected from the group ofhydroxy, (C₁-C₆) lower alkoxy, amino, —NH[(C₁-C₆) lower alkyl], or—N[(C₁-C₆) lower alkyl]₂; R₃₂ is elected from the group of hydrogen, or(C₁-C₆) lower alkyl; R₃₃ is one to three substituents selected from thegroup of hydrogen, or (C₁-C₆) lower alkyl; R₃₄ and R₃₅ are,independently, selected from the group of hydrogen, or (C₁-C₆) loweralkyl, with the proviso that R₃₄ and R₃5 taken together with thenitrogen atom to which they are attached, may form a 5 memberedunsaturated heterocycle containing 2 to 3 nitrogen atoms; X′ is O;Y′=CH₂ or X′; K=Y′ or N[(C₁-C₆) lower alkyl]; m is an integer from 1 to4; n is an integer from 1 to 4; p is an integer from 2 to 4; q is aninteger from 1 to 5; r is an integer from 1 to 2; s is an integer from 0to 1; and the pharmaceutically acceptable salts, or pro-drug formsthereof.
 3. A compound of claim 2 having the formula:

wherein R and R₄ are as defined in claim 2, or a pharmaceuticallyacceptable salt thereof.
 4. A compound of claim 2 having the formula:

wherein R and R₄ are as defined in claim 2, or a pharmaceuticallyacceptable salt thereof.
 5. A compound of claim 1 which is selected fromthe group of: a)10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid; b)(4-Methyl-piperazin-1-yl)-[10-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl-methanone; c)10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid bis-(3-dimethylamino-propyl)-amide; d)[4-(3-Dimethylaminopropyl)-piperazin-1-yl]-[10-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-methanone;e)[3-Methyl-4-(3-methyl-phenyl)-piperazin-1-yl]-[10-(2-methyl-2′-trifluoromethyl-[I,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl-methanone;f)4-[[10,11-Dihydro-10-[[2-methyl-2′-trifluoromethyl[1,1′-biphenyl]-4-yl]carbonyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]carbonyl]-1-piperazine-carboxylicacid, tert-butyl ester; g)10,11-Dihydro-10-[[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine;h)N-[(10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]guanidine;i)10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid; or j)110-[(3-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid; or apharmaceutically acceptable salt form thereof.
 6. A compound of claim 1which is selected from the group of:N-Methyl-N-[3-(dimethylamino)propyl]-10-[(3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;7,8-Dimethoxy-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl][2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]methanone;N-Methyl-[N-(3-dimethylamino)propyl]-7,8-dimethoxy-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;7,8-Dimethoxy-10-{[2-methyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl]carbonyl}-[(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]-4-piperidinone;10-{[6-Chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid;10-{[2′-Chloro-6-chloro-3-methoxy-[i,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro -5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid;10-{[6-Chloro-3-methoxy-2′-ethoxy[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine;10-{[6-Chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid;10-{[2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid;{[10-(2-Methoxy)-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-[(2S)-[(2-pyrrolidin-1-yl)methyl]pyrrolidin-1-yl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl-methanone;N-Methyl-[N-(3-dimethylamino)propyl]-10-{[2-methoxy-2′-trifluoromethyl-[, 1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-carboxamide;N-Methyl-[N-(2-dimethylamino)ethyl]-10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;[2-Chloro-4-(naphthalen-1-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone;[4-(4-Methyl-naphthalen-1-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone; Methyl10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo [2,1-c][1.4]benzodiazepine-8-carboxylate; [4-(2,5-Dimethyl-l-H-pyrrol-1-yl)-3-methoxy-phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone; Example 28[6-(Naphthalen-1-yl)-pyridin-3-yl]-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone;(6-Phenyl-pyridin-3-yl)-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone;[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3,5-dimethyl-phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone;[3-Methyl-4-(4-pyridinyl)phenyl]-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone;10-{[3,6-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine;{[10-(2-Methoxy)-2′-chloro-[1,1′-biphenyl]-4-yl]carbonyl}-[(2S)-[(2-pyrrolidin-1-yl)methyl]pyrrolidin-1-yl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl-methanone;10-[(6-Chloro-3-methoxy-2′-ethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methylpiperidin-4-yl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(Dimethylamino)propyl]-N-methyl-10-[(6-chloro-3-methoxy-2′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;[4-(3-Dimethylaminopropyl)-piperazin-1-yl]-{i 0-[4-(naphthalen-1-yl)-phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl-methanone;(4-Methyl-piperazin-1-yl)-{10-[2-chloro-[4-(naphthalen-1-yl)]phenyl]carbonyl}10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl-methanone;10-{2-Methyl-2′-trifluoromethyl-[l,1′-biphenyl]-4-yl]carbonyl}-8-(piperidine-1-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid-methyl-(1-methyl-piperidin-4-yl)-amide;[3-Methyl-4-(pyridin-4-yl)-phenyl]-{[(2S)-3-[(2-pyrrolidin-1-yl)methyl]pyrrolidin-1-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl-methanone;10-[(6-Phenyl-pyridin-3-yl)carbonyl]-N-methyl-N-(1-methyl-piperidin-4-yl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 7. A compound ofclaim 1 which is selected from the group of:[4-(3-Dimethylaminopropyl)-piperazin-1-yl]-[10-[(2′-methoxy-2-methyl-[i,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepin-3-yl]-methanone;N-[2-(Dimethylamino)ethyl]-10-{[6-chloro-3-methoxy-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3carboxamide;10-[(2′-Chloro-6-chloro-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methylpiperidin-4-yl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;{3-[4-(3-Dimethylamino-propyl)-piperazin-1-yl]carbonyl}-[4-(4-methyl-naphthalen-1-yl)phenyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl-methanone;10-{[6-(Naphthalen-1-yl)-pyridin-3-yl]carbonyl}-N-methyl-N-(1-methyl-piperidin-4-yl)-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxamide;{[10-(3,6-Dimethoxy)-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-[(2S)-[(2-pyrrolidin-1-yl)methyl]-pyrrolidin-1-yl]-l10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl-methanone;{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone;{10-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone;{10-[(2′-Methoxy-2-methyl[1l,1l′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone;{10-[(2,2′-Dimethyl[l ,l′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone; {10-[(3′-Methoxy-2-methyl[1,1l′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][l1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone;{10-[(2′-Methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone;{10-[(2-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone;{10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-5pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone;{10-[3-Methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone;{10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone;{10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone;{10-[2-Chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone;(4-Methyl-1,4-diazepan-1-yl)(10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)methanone;8. A compound of claim 1 which is selceted from the group of:{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone;{10-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone;{10-[(2′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone;{10-[(2,2′-Dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone;{10-[(3′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone;{10-[(2′-Methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone;{10-[(2-Methoxy-2′-methyl[l,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone;{10-[(6-Chloro-3,3′-dimethoxy[i,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone;{10-[3-Methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone;{10-[(2,2′-Dimethoxy[i,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone;{10-[(2,3′-Dimethoxy[i,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone;{10-[2-Chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone;N-[3-(Dimethylamino)propyl]-10-[(2′-methoxy-2-methyl[l,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(Dimethylamino)propyl]-10-[(2,2′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(Dimethylamino)propyl]-10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(Dimethylamino)propyl]-10-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(Dimethylamino)propyl]-10-[(2′-methyl[1,1-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(Dimethylamino)propyl]-10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(dimethylamino)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(dimethylamino)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 9. A compound ofclaim 1 which is selected from the group of:N-[3-(Dimethylamino)propyl]-10-[3-methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(dimethylamino)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(dimethylamino)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[2-Chloro-4-(1-naphthyl)benzoyl]-N-[3-(dimethylamino)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(Dimethylamino)propyl]-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1.4]benzodiazepine-3-carboxamide;N-[2-(Dimethylamino)ethyl]-N-methyl-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(dimethylamino)ethyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(dimethylamino)ethyi]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[2-(Dimethylamino)ethyl]-10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[2-(Dimethylamino)ethyl]-10-[(3′-methoxy-2-methyl[1l,′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[2-(Dimethylamino)ethyl]-10-[(2′-methoxy[1,1′-biphenyl]4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[2-(Dimethylamino)ethyl]-N-methyl-10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[2-(Dimethylamino)ethyl]-10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[2-(Dimethylamino)ethyl]-10-[3-methoxy-4-(1-naphthyl)benzoyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(dimethylamino)ethyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(dimethylamino)ethyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[2-Chloro-4-(1-naphthyl)benzoyl]-N-[2-(dimethylamino)ethyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(Dimethylamino)propyl]-N-methyl-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(dimethylamino)propyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(dimethylamino)propyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 10. A compound ofclaim 1 which is selcetd from the group of:N-[3-(Dimethylamino)propyl]-10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(Dimethylamino)propyl]-10-[(2,2′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,I1-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(Dimethylamino)propyl]-10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(Dimethylamino)propyl]-10-[(2′-methoxy[1,1¹′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(Dimethylamino)propyl]-N-methyl-10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(Dimethylamino)propyl]-10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(Dimethylamino)propyl]-10-[3-methoxy-4-(1-naphthyl)benzoyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(dimethylamino)propyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(dimethylamino)propyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[2-Chloro-4-(1-naphthyl)benzoyl]-N-[3-(dimethylamino)propyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone;{10-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone;{10-[(2-Methyl-2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone;{10-[(2-Methyl-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone;{10-[(2-Methyl-3′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone;{10-[(2′-Methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone;{10-[(2-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone;{10-[(6-Chloro-3-methoxy-3′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yi}[4-(1-piperidinyl)-1-piperidinyl]methanone;{10-[3-Methoxy-4-(1-naphthyl)-benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone;{10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone;or a pharmaceutically acceptable salt form thereof.
 11. A compound ofclaim 1 which is selcetewd from the group of: {10-[(2,3′-Dimethoxy-l ,I′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone;{10-[(2-Chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone;{10-[(2-Methyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]methanone;N-[3-(1H-Imidazol-1-yl)propyl]-10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2,2′-Dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(1H-imidazol-1-yl)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(1H-Imidazol-1-yl)propyl]-10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(1H-Imidazol-1-yl)propyl]-10-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(1H-Imidazol-1-yl)propyl]-10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(1H-Imidazol-1-yl)propyl]-10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(1H-imidazol-1-yl)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]4-yl)carbonyl]-N-[3-(1H-imidazol-1-yl)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(1H-lmidazol-1-yl)propyl]-10-[3-methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(1H-imidazol-1-yl)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[3-(1H-imidazol-1-yl)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[2-Chloro-4-(1-naphthyl)benzoyl]-N-[3-(1H-imidazol-1-yl)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(1H-lmidazol-1-yl)propyl]-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone;{10-[(2′-Methoxy-2-methyl[1,1′-biphenyl]4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone;{10-[(2,2′-Dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone;{10-[(3′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone;{10-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone;or a pharmaceutically acceptable salt form thereof.
 12. A compound ofclaim 1 which is selected from the group of:{10-[(2′-Methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone;{10-[(2-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone;{10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone;{10-[3-Methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolid inyl)-l -piperidinyl]methanone;{10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-y)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone;{10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone;{10-[2-Chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-l-pipe ridinyl]methanone;(10-{[2-Methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzod iazepin-3-yl)[4-(1-pyrrolidinyl)-l -piperidinyl]methanone; 10-[(2′-Methoxy-2-methyl[l , i′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2,2′-Dimethyl[1l,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][ 1,4]benzodiazepine-3-carboxamide;10-[(3′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2′-Methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[3-Methoxy-4-(1-naphthyl)benzoyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 13. A compound ofclaim 1 which is selected from the group of:10-[2-Chloro-4-(1-naphthyl)benzoyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-{[2-Methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2,2′-Dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(3′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2′-Methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[3-Methoxy-4-(1-naphthyl)benzoyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[2-Chloro-4-( 1-naphthyl)benzoyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[2-(1-Methyl-2-pyrrolidinyl)ethyl]-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(3′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-Methyl-10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-(1-methyl-4-piperidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 14. A compound ofclaim 1 which is selected from the group of:10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[3-Methoxy-4-(1-naphthyl)benzoyl]-N-methyl-N-(1-methyl-4-piperidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-Methyl-N-(1-methyl-4-piperidinyl)-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-3-pyrrolidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(3′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-3-pyrrolidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-3-pyrrolidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-Methyl-10-[(2′-methyl[l,I′-biphenyl]-4-yl)carbonyl]-N-(1-methyl-3-pyrrolidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-3-pyrrolidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-3-pyrrolidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-3-pyrrolidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[3-Methoxy-4-(1-naphthyl)benzoyl]-N-methyl-N-(1-methyl-3-pyrrolidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(1-methyl-3-pyrrolidinyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-Methyl-N-(1-methyl-3-pyrrolidinyl)-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;{4-[2-(Dimethylamino)ethyl]-1-piperazinyl}{10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{4-[2-(Dimethylamino)ethyl]-1-piperazinyl}(10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)methanone;{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(dimethylamino)ethyl]-1-piperazinyl}methanone;{4-[2-(Dimethylamino)ethyl]-1-piperazinyl}{10-[(2,2′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{4-[2-(Dimethylamino)ethyl]-1-piperazinyl}{10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;or a pharmaceutically acceptable salt form thereof.
 15. A compound ofclaim 1 which is selected from the group of:{4-[2-(Dimethylamino)ethyl]-1-piperazinyl} {10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{4-[2-(Dimethylamino)ethyl]-1-piperazinyl}{10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(dimethylamino)ethyl]-1-piperazinyl}methanone;{4-[2-(Dimethylamino)ethyl]-1-piperazinyl}{10-[3-methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(dimethylamino)ethyl]-1-piperazinyl}methanone;{10-[2-Chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(dimethylamino)ethyl]-1-piperazinyl}methanone;{10-[(2′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone;{10-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone;{10-[(3′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone;{10-[(2′-Methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone;{10-[(2-Methoxy-2′-methyl[1,1′-biphenyl]-4-y )carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone;{10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone;{10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone;{10-[3-Methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone;{10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone;{10-[2-Chloro-4-(1-naphthyl)benzoyl]-10,11-d ihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone;(10-{[2-Methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl){4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone;{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone;{10-[(2,2′-Dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone;(4-Allyl-1-piperazinyl){10-[(6-chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;or a pharmaceutically acceptable salt form thereof.
 16. A compound ofclaim 1 which is selected from the group of:(4-Allyl-1-piperazinyl){10-[(2,2′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;(4-Allyl-1-piperazinyl){10-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;(4-Allyl-1-piperazinyl){10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;(4-Allyl-1-piperazinyl){10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;(4-Allyl-1-piperazinyl){10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;(4-Allyl-1-piperazinyl){10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;(4-Allyl-1-piperazinyl){10-[(6-chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;(4-Allyl-1-piperazinyl){10-[(2,2′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;(4-Allyl-1-piperazinyl){10-[(2,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;(4-Allyl-1-piperazinyl){10-[2-chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;(4-Allyl-1-piperazinyl)(10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)methanone;(4-Allyl-1-piperazinyl){10-[3-methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;(4-Isopropyl-1-piperazinyl){10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{10-[(2,2′-Dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-isopropyl-1-piperazinyl)methanone;(4-Isopropyl-1-piperazinyl){10-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;(4-Isopropyl-1-piperazinyl){10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;(4-Isopropyl-1-piperazinyl){10-[3-methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;(4-Isopropyl-1-piperazinyl){10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-isopropyl-1-piperazinyl)methanone;{10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-isopropyl-1-piperazinyl)methanone;or a pharmaceutically acceptable salt form thereof.
 17. A compound ofclaim 1 which is selected from the group of:(4-Isopropyl-1-piperazinyl)(10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)methanone;{10-[(2,2′-Dimethoxy[1,1′-biphenyl]4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-isopropyl-1-piperazinyl)methanone;{10-[(2,3′-Dimethoxy[1,1′-biphenyl]4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-isopropyl-1-piperazinyl)methanone;{10-[2-Chloro4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-isopropyl-1-piperazinyl)methanone;{10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-isopropyl-1-piperazinyl)methanone;{4-[3-(Dimethylamino)propyl]-l -piperazinyl}{10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{4-[3-(Dimethylamino)propyl]-1-piperazinyl}{10-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{4-[3-(Dimethylamino)propyl]-1-piperazinyl}{10-[(2,2′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{4-[3-(Dimethylamino)propyl]-1-piperazinyl}{10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{4-[3-(Dimethyiamino)propyl]-1-piperazinyl}{10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{4-[3-(Dimethylamino)propyl]-1-piperazi nyl}{10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[3-(dimethylamino)propyl]-1-piperazinyl}methanone;{10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[3-(dimethylamino)propyl]-1-piperazinyl}methanone;{4-[3-(Dimethylamino)propyl]-1-piperazinyl}{10-[3-methoxy4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;({10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[3-(dimethylamino)propyl]-1-piperazinyl}methanone;{10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[3-(dimethylamino)propyl]-1-piperazinyl}methanone;{10-[2-Chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[3-(dimethylamino)propyl]-1-piperazinyl}methanone;{10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[3-(dimethylamino)propyl]-1-piperazinyl}-methanone;(10-{[2-Methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone;{10-[(2′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1pyrrolidinylmethyl)pyrrolidinyl]methanone; or a pharmaceuticallyacceptable salt form thereof.
 18. A compound of claim 1 which isselected from the group of:{10-[(2,2′-Dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone;{10-[2-Chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone;{10-[3-Methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone;{10-[(3′-Methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone;{10-[(2′-Methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone;{10-[(2′-Methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone;{10-[(2-Methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone;{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone;{10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone;{10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone;{10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone;[(3R)-3-(Dimethylamino)pyrrolidinyl](10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)methanone;[(3R)-3-(Dimethylamino)pyrrolidinyl]{10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(3R)-3-(dimethylamino)pyrrolidinyl]methanone;[(3R)-3-(Dimethylamino)pyrrolidinyl]{10-[(2,2′-dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(3R)-3-(dimethylamino)pyrrolidinyl]methanone;[(3R)-3-(Dimethylamino)pyrrolidinyl]{10-[3-methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{10-[2-Chloro-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(3R)-3-(dimethylamino)pyrrolidinyl]methanone;[(3R)-3-(Dimethylamino)pyrrolidinyl]{10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;[(3R)-3-(Dimethylamino)pyrrolidinyl]{10-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;or a pharmaceutically acceptable salt form thereof.
 19. A compound ofclaim 1 which is selected from the group of:[(3R)-3-(Dimethylamino)pyrrolidinyl]{10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;[(3R)-3-(Dimethylamino)pyrrolidinyl]{10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(3R)-3-(dimethylamino)pyrrolidinyl]methanone;{10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(3R)-3-(dimethylamino)pyrrolidinyl]methanone;N-[(1S)-2-Amino-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[(1S)-2-Amino-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-10-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[(1S)-2-Amino-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-10-[(2,2′-dimethoxy[,1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[(1S)-2-Amino-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-10-[(6-chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[(1S)-2-Amino-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-10-[(2′-methoxy-2-methyl[1,1′-biphenyl]4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;1H-Imidazol-1-yl-{10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;1H-Imidazol-1-yl-{10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;1H-Imidazol-1-yl-{10-[3-methoxy4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;1H-lmidazol-1-yl{10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(1H-imidazol-1-yl)methanone;1H-Imidazol-1-yl(10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)methanone;N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-10-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-10-[(6-chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-10-[(2,2′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 20. A compound ofclaim 1 which is selected from the group of:N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-10-[(2,2′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;tert-Butyl(5S)-6-amino-5-[({10-[(6-chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}carbonyl)amino]-6-oxohexylcarbamate;tert-Butyl(5S)-6-amino-5-[({10-[(2,2′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}carbonyl)amino]-6-oxohexylcarbamate;tert-Butyl(5S)-6-amino-5-[({10-[(6-chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}carbonyl)amino]-6-oxohexylcarbamate;{10-(3-Methoxy-4-pyridin-3-y1-benzoyl)-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepin-3-yl}-[4-(1-piperidinyl)-1-piperidinyl]-methanone;{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihyd ro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1-piperazinyl)methanone;{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-methyl-1,4-diazepan-1-yl)methanone;N-[3-(Dimethylamino)propyl]-10-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[2-(Dimethylamino)ethyl]-10-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[3-(Dimethylamino)propyl]-10-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxy-benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-piperidinyl)-1-piperidinyl]-methanone;10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-N-[3-(1H-imidazol-1-yl)propyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(1-pyrrolidinyl)-1-piperidinyl]methanone;10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-N-[2-(1-piperidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;{4-[2-(Dimethylamino)ethyl]-l -piperazinyl}{10-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}{4-[2-(4-morpholinyl)ethyl]-1-piperazinyl}methanone;(4-Allyl-1-piperazinyl){10-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}(4-isopropyl-1-piperazinyl)methanone;{4-[3-(Dimethylamino)propyl]-1-piperazinyl}{10-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[(2S)-2-(1-pyrrolidinylmethyl)pyrrolidinyl]methanone; [(3R)-3-(Dimethylamino)pyrrolidinyl]{10-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;[3-(4-Methyl-piperazine-1-carbonyl)-4H-10H-3a,5,9-triaza-benzo[f]azulen-9-yl]-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-methanone;or a pharmaceutically acceptable salt form thereof.
 21. A method oftreating disorders which are remedied or alleviated by oxytocinantagonist activity in a mammal, the method comprising administering tothe mammal in need thereof a pharmaceutically effective amount of acompound of claim 1, or a pharmaceutically acceptable prodrug formthereof.
 22. A method of claim 21 wherein the the disorder which isremedied or alleviated by oxytocin antagonist activity is selected fromthe group of preterm labor, dysmenorrhea or endometritis.
 23. A methodfor suppressing labor prior to caesarean delivery in a mammal, themethod comprising administering to the mammal in need thereof apharmaceutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt form thereof.
 24. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt form thereof., and apharmaceutically acceptable carrier or excipient.